Comparative Effectiveness Review Number 185

Tympanostomy Tubes in Children With Otitis Media

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Comparative Effectiveness Review Number 185 Tympanostomy Tubes in Children With Otitis Media Prepared for: Agency for Healthcare Research and Quality U.S. Department of Health and Human Services 5600 Fishers Lane Rockville, MD 20857 www.ahrq.gov Contract No. 290-2015-00002-I Prepared by: Brown Evidence-based Practice Center Providence, RI Investigators: Dale Steele, M.D., M.S. Gaelen P. Adam, M.L.I.S. Mengyang Di, M.D., Ph.D. Christopher Halladay, B.A., Sc.M. Ian Pan, M.A. Nathan Coppersmith, B.A. Ethan M. Balk, M.D., M.P.H. Thomas A. Trikalinos, M.D., Ph.D. AHRQ Publication 17-EHC003-EF May 2017

This report is based on research conducted by the Brown Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. 290-2015-00002-I). The findings and conclusions in this document are those of the authors, who are responsible for its contents; the findings and conclusions do not necessarily represent the views of AHRQ. Therefore, no statement in this report should be construed as an official position of AHRQ or of the U.S. Department of Health and Human Services. None of the investigators have any affiliations or financial involvement that conflicts with the material presented in this report. The information in this report is intended to help health care decisionmakers—patients and clinicians, health system leaders, and policymakers, among others—make well-informed decisions and thereby improve the quality of health care services. This report is not intended to be a substitute for the application of clinical judgment. Anyone who makes decisions concerning the provision of clinical care should consider this report in the same way as any medical reference and in conjunction with all other pertinent information, i.e., in the context of available resources and circumstances presented by individual patients. This report is made available to the public under the terms of a licensing agreement between the author and the Agency for Healthcare Research and Quality. This report may be used and reprinted without permission except those copyrighted materials that are clearly noted in the report. Further reproduction of those copyrighted materials is prohibited without the express permission of copyright holders. AHRQ or U.S. Department of Health and Human Services endorsement of any derivative products that may be developed from this report, such as clinical practice guidelines, other quality enhancement tools, or reimbursement or coverage policies, may not be stated or implied. This report may periodically be assessed for the currency of conclusions. If an assessment is done, the resulting surveillance report describing the methodology and findings will be found on the Effective Health Care Program Web site at www.effectivehealthcare.ahrq.gov. Search on the title of the report. Persons using assistive technology may not be able to fully access information in this report. For assistance contact EffectiveHealthCare@ahrq.hhs.gov. Suggested citation: Steel D, Adam GP, Di M, Halladay C, Pan I, Coppersmith N, Balk EM, Trikalinos TA. Tympanostomy Tubes in Children With Otitis Media. Comparative Effectiveness Review No. 185. (Prepared by the Brown Evidence-based Practice Center under Contract No. 290-2015-00002-I.) AHRQ Publication No. 17-EHC003-EF. Rockville, MD: Agency for Healthcare Research and Quality; May 2017. www.effectivehealthcare.ahrq.gov/reports/final.cfm. doi: https://doi.org/10.23970/AHRQEPCCER185.

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Preface The Agency for Healthcare Research and Quality (AHRQ), through its Evidence-based

Practice Centers (EPCs), sponsors the development of systematic reviews to assist public- and private-sector organizations in their efforts to improve the quality of health care in the United States. These reviews provide comprehensive, science-based information on common, costly medical conditions, and new health care technologies and strategies.

Systematic reviews are the building blocks underlying evidence-based practice; they focus attention on the strength and limits of evidence from research studies about the effectiveness and safety of a clinical intervention. In the context of developing recommendations for practice, systematic reviews can help clarify whether assertions about the value of the intervention are based on strong evidence from clinical studies. For more information about AHRQ EPC systematic reviews, see www.effectivehealthcare.ahrq.gov/reference/purpose.cfm. AHRQ expects that these systematic reviews will be helpful to health plans, providers, purchasers, government programs, and the health care system as a whole. Transparency and stakeholder input are essential to the Effective Health Care Program. Please visit the Web site (www.effectivehealthcare.ahrq.gov) to see draft research questions and reports or to join an email list to learn about new program products and opportunities for input. If you have comments on this systematic review, they may be sent by mail to the Task Order Officer named below at: Agency for Healthcare Research and Quality, 5600 Fishers Lane, Rockville, MD 20857, or by email to epc@ahrq.hhs.gov. Sharon B. Arnold, Ph.D. Arlene S. Bierman, M.D., M.S. Acting Director Director Agency for Healthcare Research and Quality Center for Evidence and Practice Improvement Agency for Healthcare Research and Quality Stephanie Chang, M.D., M.P.H. Lionel L. Bañez, M.D. Director Task Order Officer Evidence-based Practice Center Program Center for Evidence and Practice Improvement Center for Evidence and Practice Improvement Agency for Healthcare Research and Quality Agency for Healthcare Research and Quality

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Key Informants In designing the study questions, the EPC consulted several Key Informants who represent the end-users of research. The EPC sought the Key Informant input on the priority areas for research and synthesis. Key Informants are not involved in the analysis of the evidence or the writing of the report. Therefore, in the end, study questions, design, methodological approaches, and/or conclusions do not necessarily represent the views of individual Key Informants. Key Informants must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Because of their role as end-users, individuals with potential conflicts may be retained. The TOO and the EPC work to balance, manage, or mitigate any conflicts of interest. The list of Key Informants who provided input to this report follows: Margaretha Casselbrandt, M.D., Ph.D.* Department of Pediatric Otolaryngology Children's Hospital of Pittsburgh Pittsburgh, PA Alison Grimes, Au.D.* Audiology Department UCLA Medical Center Los Angeles, CA David Hoelting, M.D. Pender Medical Clinic Pender Community Hospital Pender, NE

Alison Kelly, B.S.N., R.N., C.P.E.N. Hasbro Children’s Hospital Providence, RI Josiah Morse, M.P.H. Washington State Health Technology Assessment Program Olympia, WA Richard Rosenfeld, M.D., M.P.H., FAAP* Department of Otolaryngology SUNY Downstate Medical Center Brooklyn, NY David E. Tunkel, M.D.* Director of Pediatric Otolaryngology Johns Hopkins University School of Medicine Baltimore, MD

*Provided input on draft report.

Technical Expert Panel In designing the study questions and methodology at the outset of this report, the EPC consulted several technical and content experts. Broad expertise and perspectives were sought. Divergent and conflicting opinions are common and perceived as healthy scientific discourse that results in a thoughtful, relevant systematic review. Therefore, in the end, study questions, design, methodologic approaches, and/or conclusions do not necessarily represent the views of individual technical and content experts. Technical Experts must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Because of their unique clinical or content expertise, individuals with potential conflicts may be retained. The TOO and the EPC work to balance, manage, or mitigate any potential conflicts of interest identified.

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The list of Technical Experts who provided input to this report follows: Alison Grimes, Au.D.* Audiology Department UCLA Medical Center Los Angeles, CA David Hoelting, M.D. Pender Medical Clinic Pender Community Hospital Pender, NE Howard J. Hoffman, B.S., M.A.* Epidemiology and Statistics Program Division of Scientific Programs National Institute on Deafness and Other Communication Disorders National Institutes of Health U.S. Department of Health and Human Services Bethesda, MD

Richard Rosenfeld, M.D., M.P.H., FAAP* Department of Otolaryngology SUNY Downstate Medical Center Brooklyn, NY Lorry Rubin, MD* Hofstra North Shore-LIJ School of Medicine Hempstead, NY David E. Tunkel, M.D.* Director of Pediatric Otolaryngology Johns Hopkins University School of Medicine Baltimore, MD Roderick Venekamp, M.D., M.Sc., Ph.D.* University Medical Center Utrecht Julius Center for Health Sciences and Primary Care & Department of Otorhinolaryngology The Netherlands

*Provided input on draft report.

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Peer Reviewers Prior to publication of the final evidence report, EPCs sought input from independent Peer Reviewers without financial conflicts of interest. However, the conclusions and synthesis of the scientific literature presented in this report do not necessarily represent the views of individual reviewers. Peer Reviewers must disclose any financial conflicts of interest greater than $10,000 and any other relevant business or professional conflicts of interest. Because of their unique clinical or content expertise, individuals with potential nonfinancial conflicts may be retained. The TOO and the EPC work to balance, manage, or mitigate any potential nonfinancial conflicts of interest identified. The list of Peer Reviewers follows: Christine Dollaghan, Ph.D. School of Behavioral and Brain Sciences University of Texas at Dallas Richardson, TX Sharon Meropol, M.D., Ph.D. Case Western Reserve University School of Medicine Rainbow Babies and Children’s Hospital Cleveland, OH

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Tympanostomy Tubes in Children With Otitis Media Structured Abstract Objectives. The objectives for the systematic review are to synthesize information on the effectiveness of tympanostomy tubes (TT) in children with chronic otitis media with effusion and recurrent acute otitis media, summarize the frequency of adverse effects or complications associated with TT placement, synthesize information on the necessity for water precautions in children with TT, and assess the effectiveness of available treatments for otorrhea in children who have TT. Data sources. We conducted literature searches in MEDLINE®, the Cochrane Central Trials Registry and Cochrane Database of Systematic Reviews, Embase®, and CINAHL®. Additionally, we perused the reference lists of published relevant clinical practice guidelines and narrative and systematic reviews, and examined Scientific Information Packages from manufacturers. Citations were independently screened by two researchers. Review methods. Each study was extracted by one methodologist and confirmed by at least one other methodologist. Data were extracted into customized forms in the Systematic Review Data Repository (SRDR) online system. All included studies were summarized in narrative form and in summary tables. We conducted random effects meta-analyses of comparative studies that were sufficiently similar in population, interventions, and outcomes, and network meta-analyses to compare treatment alternatives across studies. Specific methods and metrics (summary measures) meta-analyzed were chosen based on available reported study data. The PROSPERO protocol registration number is CRD42015029623. Results and conclusions. The literature search yielded 13,334 citations, of which 172 articles are included in the report. Overall, the evidence suggests that TT placed in children with persistent middle-ear effusion improve hearing at 1 to 3 months compared to watchful waiting, but there is no benefit at 12 to 24 months. TT did not consistently improve language, cognition, behavior, or quality of life. However, evidence is sparse, limiting definitive conclusions, and is applicable only to otherwise healthy children. The current evidence base provides little guidance for the treatment of children with cleft palate or Down syndrome. Children with recurrent acute otitis media may have fewer episodes after TT placement, but the evidence base is limited and there is insufficient evidence to assess the impact on quality of life. The benefits of TT placement must be weighed against a variety of adverse events. There is no compelling evidence for children with TT to avoid swimming or bathing, or use earplugs or bathing caps. Should otorrhea develop, the evidence supports topical treatment rather than oral antibiotics or watchful waiting.

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Contents Executive Summary ................................................................................................................ ES-1 Introduction ................................................................................................................................... 1

Background and Objectives ........................................................................................................ 1 Key Questions ............................................................................................................................. 2 Analytic Frameworks .................................................................................................................. 3

Methods .......................................................................................................................................... 6 Eligibility Criteria ....................................................................................................................... 6

Populations .............................................................................................................................. 6 Interventions/Exposures .......................................................................................................... 6 Comparators ............................................................................................................................ 7 Outcomes ................................................................................................................................ 7 Timing ..................................................................................................................................... 7 Setting ..................................................................................................................................... 7 Study Design ........................................................................................................................... 8

Evidence Identification ............................................................................................................... 8 Data Extraction and Data Management ...................................................................................... 8 Assessment of Methodological Risk of Bias of Individual Studies ............................................ 9 Data Synthesis ............................................................................................................................. 9 Grading the Strength of Evidence ............................................................................................. 10 Assessing Applicability ............................................................................................................ 11

Results .......................................................................................................................................... 12 Key Question 1 ......................................................................................................................... 13

Eligible Studies ..................................................................................................................... 14 Outcomes: Nonrandomized Comparative Studies ................................................................ 20 Hearing Outcomes: RCTs ..................................................................................................... 20 Duration of Effusion ............................................................................................................. 26 Quality of Life and Patient-Centered Outcomes ................................................................... 29

Key Question 2 ......................................................................................................................... 31 Description of Comparative Studies ..................................................................................... 31 Outcomes .............................................................................................................................. 32 Key Question 2a .................................................................................................................... 33

Key Question 3 ......................................................................................................................... 34 Key Question 4 ......................................................................................................................... 35

Description of Comparative Studies ..................................................................................... 36 Risk of Bias ........................................................................................................................... 38 Outcomes .............................................................................................................................. 38

Key Question 5 ......................................................................................................................... 40 Risk of Bias ........................................................................................................................... 40 Outcomes .............................................................................................................................. 41

Discussion..................................................................................................................................... 45 Overall Summary and Strength of Evidence ............................................................................ 45 Limitations ................................................................................................................................ 50 Future Research Recommendations .......................................................................................... 51 Conclusions ............................................................................................................................... 52

References .................................................................................................................................... 53

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Tables Table A. Probabilities (percent) that an intervention is among the three most effective with respect to early hearing thresholds .......................................................................................... ES-10 Table B. Probabilities (percent) that an intervention is among the two most effective with respect to late hearing thresholds ........................................................................................................ ES-12 Table C. Median percentage of patients and ears with adverse events associated with TT placement ................................................................................................................................ ES-16 Table D. RCTs: Water precautions—one or more episodes of otorrhea ............................... ES-17 Table E. Probabilities (percent) that an intervention is among the three most effective with respect to clinical resolution of otorrhea ................................................................................. ES-19 Table F. Summary of conclusions and associated strength of evidence dispositions Table 1. Summary of randomized controlled trials (RCTs) ......................................................... 16 Table 2. Summary of nonrandomized comparative studies18 Table 3. Differences in early hearing thresholds (in dB, 1-3 months) .......................................... 21 Table 4. Probabilities (percent) that an intervention ranks as the i-th most effective with respect to early hearing thresholds ............................................................................................................ 22 Table 5. Probabilities (percent) that an intervention is among the three most effective with respect to early hearing thresholds ................................................................................................ 22 Table 6. Differences in late hearing thresholds (in dB, 1-3 months) ............................................ 24 Table 7. Probabilities (percent) that an intervention ranks as the i-th most effective with respect to late hearing thresholds .............................................................................................................. 24 Table 8. Probabilities (percent) that an intervention is among the two most effective with respect to late hearing thresholds .............................................................................................................. 25 Table 9. Probabilities (percent) that an intervention is among the two most effective with respect to duration of MEE ....................................................................................................................... 28 Table 10. Cognitive, verbal, behavioral, and quality of life outcomes ......................................... 30 Table 11. Adverse events associated with TT placement ............................................................. 34 Table 12. RCTs: Water precautions—one or more episodes of otorrhea .................................... 37 Table 13. NRCSs: Water precautions—one or more episodes of otorrhea .................................. 37 Table 14. Effectiveness of various interventions to treat TT otorrhea ......................................... 40 Table 15. Network meta-analysis of interventions for otorrhea ................................................... 42 Table 16. Probabilities (percent) that an intervention ranks as the i-th most effective with respect to clinical resolution of otorrhea ................................................................................................... 42 Table 17. Quality of life outcomes ............................................................................................... 44 Table 18. Strength of evidence assessment................................................................................... 47

Figures Figure A. TT in children with chronic OME or recurrent AOM (Key Questions 1, 2, and 3) . ES-3 Figure B. Need for water precautions in children with TT (Key Question 4) .......................... ES-4 Figure C. Treatment of otorrhea in children with TT (Key Question 5) .................................. ES-4 Figure D. Literature flow diagram ............................................................................................ ES-8 Figure E. Network graph of comparators for early (1 to 3 months) hearing thresholds ........... ES-9 Figure F. Early (1 to 3 months) decrease (improvement) in mean hearing thresholds compared with watchful waiting ............................................................................................................. ES-10 Figure G. Network graph of comparators for late (12 to 24 months) hearing thresholds ....... ES-11

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Figure H. Late (12 to 24 months) decrease (improvement) in mean hearing thresholds compared with watchful waiting ............................................................................................................. ES-12 Figure I. Nonrandomized comparative studies only, children with one or more episodes of otorrhea ......................................................................................................................................... 18 Figure J. Network of treatment comparisons (RCTs) ................................................................... 19 Figure K. Relative effectiveness of interventions compared to watchful waiting or placebo therapy........................................................................................................................................... 20 Figure L. Relative effectiveness of interventions compared to treatment with oral antibiotics ... 21 Figure 1. TT in children with chronic OME or recurrent AOM (Key Questions 1, 2, and 3) ........ 4 Figure 2. Need for water precautions in children with TT (Key Question 4) ................................. 4 Figure 3. Treatment of otorrhea in children with TT (Key Question 5) ......................................... 5 Figure 4. Literature flow diagram ................................................................................................. 13 Figure 5. Evidence graph for the 16 RCTs ................................................................................... 14 Figure 6. Network graph for early (1-3 months) comparisons for hearing thresholds ................. 21 Figure 7. Early (1 to 3 months) decrease (improvement) in mean hearing thresholds compared with watchful waiting ................................................................................................................... 23 Figure 8. Network diagram of late (12-24 months) comparisons for hearing thresholds ............. 23 Figure 9. Late (12-24 months) decrease (improvement) in mean hearing thresholds compared with watchful waiting ................................................................................................................... 25 Figure 10. Network graph for duration of middle ear effusion..................................................... 28 Figure 11. Decrease (improvement) in mean duration of middle ear effusion compared with watchful waiting............................................................................................................................ 28 Figure 12. NRCSs only, children with one or more episodes of otorrhea…………………. 76 Figure 13. Network of treatment comparisons (RCTs) ................................................................ 41 Figure 14. Relative effectiveness of various interventions compared to watchful waiting or placebo Figure 15. Relative effectiveness of interventions compared to oral antibiotics

Appendixes Appendix A. Literature Search Appendix B. Excluded Studies Appendix C. Study Design Appendix D. Arm Details Appendix E. Baseline Characteristics Appendix F. Risk of Bias Appendix G. Patient-Centered and Quality of Life Outcomes Appendix H. Harms Appendix I. Network Meta-Analysis Model, Inconsistency Analysis Results, and Illustrative Trace and Posterior Density Plots

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Executive Summary Background and Objectives

Otitis media is often preceded by a viral upper respiratory tract infection that causes Eustachian tube obstruction, negative middle ear pressure, and accumulation of fluid in the normally air-filled space of the middle ear. Acute otitis media (AOM) is defined as the presence of fluid in the middle ear with signs and symptoms of an acute infection, such as fever and ear pain. Otitis media with effusion (OME) is defined as the presence of fluid in the middle ear behind an intact tympanic membrane without signs and symptoms of an acute infection. 1,2 OME is defined as chronic OME, if effusion persists for 3 months or longer.1 Acute otitis media and chronic OME have shared causes. Children with chronic OME are prone to recurrent AOM episodes, and after an AOM episode all children have OME for some time.3 Chronic OME can result in hearing deficits, which put a child at risk for speech and language delays, behavioral changes, and poor academic achievement. Recurrent AOM has been shown to impact quality of life for patients and their caregivers.4

Certain children, including those with Down syndrome and cleft palate, have a very high risk for middle ear disease. The American Academy of Otolaryngology–Head and Neck Surgery (AAO-HNS) clinical practice guideline (CPG) identifies a subpopulation of children who may be at increased risk for speech, language, or learning problems from otitis media because of baseline sensory, physical, cognitive, or behavioral factors.1,5

Myringotomy with TT placement is the most common ambulatory surgery performed on children in the United States6, with 667,000 TT placed in children under the age of 15 in 2006.7

The proceedings of the National Summit on Overuse, convened in 2012, based on sample of continually enrolled children into a treatment pathways database and a Medicaid database, reported that 2.5 percent of all U.S. children 2 years old and older had TT inserted in 2010.8

The effectiveness of TT for chronic OME and recurrent AOM is likely influenced by the many factors that affect the prognosis for middle ear disease in children, including current age, age at first diagnosis, frequency of respiratory tract infections, and day care exposure.9

The AAO-HNS CPG recommends that clinicians offer TT to children with recurrent AOM who have middle ear effusion at the time of assessment for tube candidacy, and that clinicians do not perform TT insertion when middle ear effusion is not present.1

TT placement may result in acute otorrhea in some patients and conversely watchful waiting may result in continued episodes of recurrent AOM, which may include tympanic membrane perforation and otorrhea.

In children with TTs, episodes of otorrhea that reflect acute bacterial infection may be otherwise asymptomatic and less troublesome than AOM episodes in children with intact eardrums.10 However, otorrhea may be associated with a foul odor, fever, or pain, and it may negatively affect quality of life. Treatment is aimed at eradicating bacterial infection and reducing the duration and severity of symptoms.11

The objectives for this systematic review are to synthesize information on the effectiveness of TT in children with chronic otitis media with effusion and recurrent acute otitis media, summarize the frequency of adverse effects or complications associated with TT placement, synthesize information on the necessity for water precautions in children with TT, and assess the effectiveness of available treatments for otorrhea in children who have TT.

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Key Questions With input from clinical experts during Topic Refinement, and from the public, during a

public review period, we developed the following Key Questions (KQs) and study eligibility criteria.

Key Question 1: For children with chronic otitis media with effusion, what is the effectiveness of TT, compared to watchful waiting, on resolution of middle ear effusion, hearing and vestibular outcomes, quality of life, and other patient-centered outcomes?

a. What factors (such as age, age of onset, duration of effusion, comorbidities, and sociodemographic risk factors) predict which children are likely to benefit most from the intervention?

b. Does obtaining a hearing test help identify which children are more likely to benefit from the intervention?

Key Question 2: For children with recurrent acute otitis media, what is

the effectiveness of TT, compared to watchful waiting with episodic or prophylactic antibiotic therapy, on the frequency and severity of otitis media, quality of life, and other patient-centered outcomes?

a. What factors (such as age, age of onset, number of recurrences, presence of persistent middle ear effusion, comorbidities, sociodemographic risk factors, history of complications of acute otitis media, antibiotic allergy or intolerance) predict which children are likely to benefit most from the intervention?

Key Question 3: What adverse events, surgical complications, and

sequelae are associated with inserting TT in children with either chronic otitis media with effusion or recurrent acute otitis media?

Key Question 4: Do water precautions reduce the incidence of TT otorrhea or affect quality of life?

Key Question 5: In children with TT otorrhea, what is the comparative effectiveness of topical antibiotic drops versus systemic antibiotics or watchful waiting on duration of otorrhea, quality of life, or need for tube removal?

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Analytic Frameworks The analytic frameworks in Figures A through C describe the specific linkages associating

the populations of interest, exposures, modifying factors, and outcomes of interest in the assessment of studies that examine the association between TT placement, intermediate and final health outcomes, and harms (KQs 1, 2 and 3; Figure A); need for water precautions (KQ 4; Figure B); and treatment of otorrhea (KQ 5; Figure C).

Figure A. TT in children with chronic OME or recurrent AOM (Key Questions 1, 2, and 3)

OME=otitis media with effusion; AOM=acute otitis media; TT=tympanostomy tubes; KQ=Key Question

Quality of life and patient-centered outcomes

Global and otitis-specific child andparental quality of life

Speech and language outcomes Educational achievement Behavioral outcomes

Adverse events

• Anesthetic and surgical• Otorrhea • Blockage of tube lumen• Granulation tissue• Premature extrusion• TT displacement into middle ear• Persistent perforation• Myringosclerosis• Atrophy, atelectasis or retraction• Worsened hearing thresholds

Tympanostomy tube placement(+/- adenoidectomy)

(KQ 3) Intermediate outcomes

Middle ear effusion prevalence (KQ 1) Recurrent AOM/otorrhea (KQ 2) Hearing and vestibular outcomes (KQ 1) Behavioral outcomes Antibiotic use Need for TT reinsertion

Children with chronic OME and/or

recurrent AOM

(KQ 1, KQ 2)

Modifiers of comparative effectiveness• Age, age of onset (KQ1a, KQ2a)

• Duration of middle ear effusion (KQ1, KQ2)

• Frequency of recurrent AOM (KQ 2a)

• Complications of AOM (KQ2)

• Antibiotic allergy or intolerance (KQ2)

• Hearing testing (KQ1b,)

• Comorbidities (KQ1a, KQ2a)

• Sociodemographic risk factors (KQ1a, KQ2a)

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Figure B. Need for water precautions in children with TT (Key Question 4)

OME=otitis media with effusion; AOM=acute otitis media; QoL= Quality of Life Figure C. Treatment of otorrhea in children with TT (Key Question 5)

OME=otitis media with effusion; AOM=acute otitis media; QoL= Quality of Life; TT=tympanostomy tube

Methods The Brown Evidence-based Practice Center (EPC) conducted this review based on a

systematic review of the published scientific literature using established methodologies as outlined in the Agency for Healthcare Research and Quality’s (AHRQ) Methods Guide for

Water precautions

Children with chronic OME and/or

recurrent AOM

with

Tympanostomy tubes

Intermediate outcomes

Otorrhea, incidence and duration

Final health outcomes

Global and otitis-specific child and parental QoL

(KQ 4)

Children with chronic OME and/or

recurrent AOM after TT placement

with

Otorrhea

Topical antibiotic drops

(Treatment)(KQ 5)

Intermediate outcomes

Duration of otorrhea Need for TT removal

Final health outcomes

Global and otitis-specific child and parental QoL

Adverse events

• Ototoxicity• Allergic reactions

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Comparative Effectiveness Reviews.12 The PROSPERO protocol registration number is CRD42015029623.

Eligibility Criteria We use the Population, Intervention, Comparator, Outcomes, and Designs (PICOD)

formalism to define the characteristics of the eligible studies for this review.

Populations For all KQs, studies of children and adolescents from 1 month to 18 years old were eligible.

Subpopulations of interest included children at high risk of recurrent AOM or OME, such as children with Down syndrome, cleft palate, other craniofacial anomalies, and primary ciliary dyskinesia; and children at high risk of adverse clinical or developmental outcomes, such as those with preexisting hearing loss, speech and language problems, or developmental disorders. We were also interested in the population of children who have sociodemographic risk factors, such as day care exposure or low socioeconomic status.

For KQ 1, we included studies of children with chronic OME. We preferred the standard definition of effusion that persists for at least three months,1 but included results based on studies’ alternative definitions if our preferred one was not reported. We excluded children with chronic suppurative otitis media since it is usually associated with a persistently perforated tympanic membrane.

For KQ 2, we included children with recurrent AOM with or without middle ear effusion, defined as three or more well-documented and separate AOM episodes in the past 6 months or at least four well-documented and separate AOM episodes in the past 12 months with at least one in the past 6 months.1 For studies that did not report the preferred definition, we recorded the study specific definition.

For KQ 3 and 4, we included studies in children with TT placed for OME or AOM. For KQ 5, we included studies of symptomatic or asymptomatic children with acute TT otorrhea beyond the immediate postoperative period. We defined the immediate postoperative period as 30 days after surgery, but included studies reporting results near that period (e.g., 28 days, 4 weeks).

Interventions/Exposures For KQs 1, 2 and 3, we considered all studies that included myringtomy with TT placement,

with or without adenoidectomy. Tubes were classified as short-term tubes (generally in place for 10-18 months) and long-term tubes (which typically remain in place for several years).

In KQ 4, we distinguished three categories of interventions; avoidance of swimming or head immersion while bathing, canal occlusion methods (e.g. earplugs or headbands), and postexposure prophylaxis using ototopical antibiotics.

KQ 5 compares ototopical preparations, and includes products approved by the U.S. Food and Drug Administration (FDA) (i.e., ofloxacin otic 0.3%, ciprofloxacin 0.3% and dexamethasone 0.1%), and other non–FDA-approved agents, such as hydrocortisone, bacitracin, and colistin.

Comparators For KQ 1, comparisons of primary interest were watchful waiting or adenoidectomy.

Comparators for KQ 2 included watchful waiting, systemic or topical antibiotic therapy for recurrent episodes of AOM, prophylactic antibiotics, and adenoidectomy. KQ 3 did not address

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comparative harms. In KQ 4, comparators included no water precautions with or without avoidance of higher risk activities (e.g. diving or underwater swimming), and ear plugs or swimming caps. The primary comparators for KQ5 were watchful waiting and oral antibiotic therapy.

Outcomes For KQs 1 and 2, which address the effectiveness of TT, we considered intermediate

outcomes, including the prevalence of middle ear effusion, measures of hearing and vestibular function, such as improved hearing thresholds (audibility), tests of auditory perception and discrimination (clarity), and balance and coordination (vestibular function). For KQ 2, measures of recurrent AOM, including otorrhea were extracted.

Quality of life and patient-centered outcomes were considered, including global and otitis-specific child and parental quality of life, speech and language outcomes, educational achievement, behavioral outcomes such as disobedience, enuresis, or tantrums.

The following outcomes were extracted for KQ 3: Intraoperative and immediate postoperative anesthetic and surgical adverse events, otorrhea beyond the postoperative period, blockage of the tube lumen, granulation tissue, premature extrusion, TT displacement into the middle ear, persistent perforation of the tympanic membrane, myringosclerosis, tympanic membrane atrophy, atelectasis and retraction pockets, worsened hearing thresholds, and other reported (plausibly related to tubes).

Outcomes for KQ 4 included final health and patient-centered outcomes related to child and parental quality of life and intermediate outcomes related to the incidence and duration of otorrhea. Outcomes evaluated relating to KQ 5 (treatment of otorrhea) included global and otitis-specific child and parental quality of life, duration of otorrhea, and need for removal of TT.

Timing We included studies with any duration of followup.

Setting We included studies performed in both primary and specialty care settings.

Study Design We evaluated published, peer-reviewed studies only. For KQs 1, 2, 4, and 5, we included

randomized comparative trials and nonrandomized comparative studies, prospective and retrospective where treatment was assigned on a per patient basis. Studies with per ear assignment were excluded (e.g. tubes placed by design in one ear only). For KQ 3, we included prospective surgical single group studies enrolling at least 50 subjects (including arms treated with TT that were part of randomized controlled trials [RCTs] or nonrandomized comparative studies [NRCSs]) and population based retrospective single group studies (registry studies) with at least 1000 subjects.

Searching for the Evidence We conducted literature searches of all studies in MEDLINE®, the Cochrane Central Trials

Registry and Cochrane Database of Systematic Reviews, Embase®, and CINAHL® databases (details in Appendix A of the full report). The last search was run on May 19, 2016. Additionally, we perused the reference lists of published clinical practice guidelines, relevant

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narrative and systematic reviews, and Scientific Information Packages from manufacturers. Citations were independently screened by two researchers in the open-source, online software Abstrackr (http://abstrackr.cebm.brown.edu/).

Data Extraction and Data Management Each study was extracted by one methodologist and confirmed by at least one other

methodologist. Data was extracted into customized forms in the Systematic Review Data Repository (SRDR) online system (http://srdr.ahrq.gov). Excluded studies are listed in Appendix B of the full report. Details of included studies are summarized in Appendix C, D and E of the full report.

Assessment of Risk of Bias of Individual Studies We assessed the methodological quality of each study based on predefined criteria. For

RCTs, we used the Cochrane risk of bias tool.13 For observational studies, we used relevant questions from the Newcastle Ottawa Scale.14

Data Synthesis All included studies were summarized in narrative form and in summary tables that record

the important features of the study populations, design, intervention, outcomes, and results. We performed network meta-analysis of clinical outcomes to compare treatment alternatives

across studies for KQs 1 and 5. We also conducted pairwise comparisons by means of random effects meta-analyses of comparative studies. Specific methods and metrics (summary measures) meta-analyzed were chosen based on available, reported study data. When available, these were summarized as odds ratios of categorical outcomes and net change of continuous outcomes (e.g., mean hearing thresholds). Statistical heterogeneity was explored qualitatively. We explored subgroup differences within across studies based on the list of comparisons described in the KQs.

Grading the Strength of Evidence We graded the strength of evidence (SOE) as per the AHRQ Methods Guide on assessing the

strength of evidence.15

Assessing Applicability We assessed the direct applicability within and across studies with reference to children with

specific comorbidities (Down syndrome, cleft palate, etc.), and whether interventions and comparators are used in current practice.

Results The literature search yielded 10,129 citations (Figure D). We identified 481 of these as

potentially relevant full-text studies, and retrieved them for further evaluation. Overall, 306 full text articles did not meet eligibility criteria (see Appendix B of the full report for a list of rejected articles along with reasons for rejection); thus 184 articles are included in this report.

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A trial registry search did not turn up any completed trial that was not already identified through literature searches. As shown in Figure D, the majority of included publications (n=98) related to KQ3, with 50 related to KQ1. There is a relative paucity of studies available for the other KQs.

Figure D. Literature flow diagram

CINAHL = Cumulative Index to Nursing and Allied Health Literature; KQ = Key Question; NRCS = nonrandomized comparative study; RCT = randomized controlled trial; Some publications reported data from the same study. The KQ3 publications included 70 cohorts, 12 NRCSs and 3 RCTs (from which the cohort most closely matching usual care was extracted). Detailed reasons for exclusion of studies reviewed in full text but not considered further are presented in Appendix B of the full report.

Key Question 1 We identified 54 publications Of these, there were 29 papers reporting results of 16 RCTs.

There were 24 publications reporting 24 NRCSs that assessed the effectiveness of TT in pediatric patients with chronic middle ear effusion. These studies evaluated multiple interventions (TT, TT with adenoidectomy, myringotomy with adenoidectomy, myringtomy alone, adenoidectomy alone, oral antibiotic prophylaxis, and watchful waiting). Two studies

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included at least some patients with recurrent AOM with or without persistent middle ear effusion.

Randomized Comparative Studies Hearing thresholds were measured in 16 RCTs. In 10 of these, mean hearing thresholds were

reported by arm at various time points. For the network meta-analysis of these RCTs, we classified hearing thresholds obtained at one to three months as “early”. Similarly, hearing thresholds obtained between 12 and 24 months where were classified “late”. Not all studies had interventions at both “early” and “late” time points. Thus, the network of comparators differs for “early” and “late” comparisons. Figure E shows the topology of the network for early hearing thresholds at 1 to 3 months. Such network plots are a visual representation of the evidence base.

Figure E. Network graph of comparators for early (1 to 3 months) hearing thresholds

The network plot consists of nodes representing the interventions being compared and edges representing the available direct comparisons. The number of studies that include each comparison is indicated next to each edge (connecting lines with thickness proportional to this number).

Figure F illustrates the effectiveness of various interventions at 1 to 3 months, compared with watchful waiting. Mean hearing thresholds improved (decreased) by average of 9.1 dB following TT, and by 10 dB following TT with adenoidectomy. Credible intervals for these effects exclude

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zero. The credible intervals for comparisons between watchful waiting and myringotomy alone, myringotomy with adenoidectomy, and oral antibiotic prophylaxis were wide.

Figure F. Early (1 to 3 months) decrease (improvement) in mean hearing thresholds compared

with watchful waiting

TT= tympanostomy tubes; CrI=Credible Interval

As shown in Table A, the strategies with the highest probability of being among the three

most effective interventions with respect to early improvements in hearing thresholds were TT, TT with adenoidectomy, and myringotomy with adenoidectomy.

Table A. Probabilities (percent) that an intervention is among the three most effective with respect to early hearing thresholds

Intervention Probability (%) of Being Among the 3 Most

Effective Interventions

Probability (%) of Being Among the 3 Least

Effective Interventions TT 97 3 TT + Adenoidectomy 96 4 Myringotomy 8 92 Myringotomy +

Adenoidectomy 91 9

Antibiotic Prophylaxis 6 94 Watchful Waiting 1 99

TT= tympanostomy tubes

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Five RCTs reported hearing thresholds at 12 to 24 months. Figure G shows the topology of the network of comparisons at this time interval.

Figure G. Network graph of comparators for late (12 to 24 months) hearing thresholds

The network plot consists of nodes representing the interventions being compared and edges representing the available direct comparisons. The number of studies that include each comparison is indicated next to each edge (connecting lines with thickness proportional to this number.

As shown in Figure H, by 12 to 24 months, the mean difference in hearing thresholds for TT alone, compared to watchful waiting was 0 dB (95% CrI [credible interval] -4 to 3). Compared to watchful waiting, myringotomy with adenoidectomy and TT with adenoidectomy have better hearing outcomes by about 4 dB, but the 95 percent credible intervals include zero.

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Figure H. Late (12 to 24 months) decrease (improvement) in mean hearing thresholds compared with watchful waiting

TT= tympanostomy tubes; CrI=Credible Interval

As can be seen in Table B, TT with adenoidectomy and myringotomy with adenoidectomy

were the two most effective strategies with respect to late hearing thresholds. TT alone, antibiotic prophylaxis, and watchful waiting were among the three least effective ones.

Table B. Probabilities (percent) that an intervention is among the two most effective with respect to late hearing thresholds

Intervention Probability (%) of Being Among the 2 Most

Effective Interventions

Probability (%) of Being Among the 3 Least

Effective Interventions TT 5 95 TT + Adenoidectomy 92 8 Myringotomy +

Adenoidectomy 88 12

Antibiotic Prophylaxis 10 90 Watchful Waiting 4 96

The results for the studies that reported measuring hearing thresholds, but did not report mean hearing thresholds are summarized in the full report.

A network meta-analysis of the mean duration of middle ear effusion is presented in the full report.

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Nonrandomized Comparative Studies The nonrandomized comparative studies (NRCSs) are summarized in the full report. The

NRCSs evaluated special populations and are summarized here. Six studies reported results in the populations with comorbidities of interest, including cleft palate/lip and primary ciliary dyskinesia. Three studies (two in cleft palate and one in primary ciliary dyskinesia) compared TT placement with nonsurgical treatment, while one study compared early versus delayed TT in different settings. Two studies assessed the effects of TT and cleft repairing versus cleft repairing alone. Hearing thresholds reported as pure tone averages were reported in four studies. In patients with cleft palate/lip and primary ciliary dyskinesia, respectively, average hearing threshold was lower in TT than non-surgical control, but the difference was not significant. TT in addition to cleft repair improved hearing thresholds with unknown significance. The improvement by early (mean age 3 months) compared to delayed (mean age 40.8 months or not at all in two subjects) TT procedures in patients with cleft palate was marginally significant (P=0.05 for ears with better hearing and P=0.10 for ear with worse hearing). The rate of normal hearing, defined as hearing threshold < 20 dB bilaterally, was significantly higher in TT than control (P <0.05).

Quality of Life and Patient-Centered Outcomes Eight studies (five RCTs, three NRCSs, and one that combined both designs) in 12 papers

reported on 119 quality of life and patient-centered outcomes (cognitive, language, and behavioral) in 1665 children over multiple time points and arms. These studies reported only 14 outcomes with significant results. In general, the results were not significant and varied in magnitude and direction, even across subscales of the same test. Only two studies reported specifically on quality of life outcomes: Paradise reported on measures of parental stress at various ages, and Vlastos reported on pediatric health related quality of life. Neither found any significant differences. Full details for all outcomes are in Appendix G of the full report.

Key Question 2 We identified 8 publications, reporting 7 RCTs and 2 NRCSs. The Matilla 2003 paper

reported two groups, an RCT which randomly allocated treatment in 137 patients, and a NRCS in which parental choice determined treatment in169 patients. Three RCTs compared TT placement with daily oral antibiotic prophylaxis. Two of these studies included a comparison with placebo and the third compared TT placement with no treatment. The effectiveness of TT alone versus TT with adenoidectomy was evaluable in three studies.

Randomized Comparative Studies

Frequency and Severity of Recurrent Acute Otitis Media The majority of studies were done prior to widespread use of the conjugate pneumococcal

vaccine, in an era where antibiotic resistance was less common, and prophylactic oral antibiotic therapy was more commonly used in clinical practice. Results are summarized by comparison below.

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TT Versus Placebo or No Treatment Gonzalez 1986 reported that in the placebo group three of 20 children had no further

episodes of AOM, compared to 12 of 22 in the TT group (P = 0.01, an attack rate of 2.0 in the placebo group, compared to 0.86 in the TT group (P = 0.006). In a post-hoc subgroup comparison of children who had middle ear effusion upon entering the study, attack rate and number of patients who had no further bouts of AOM was significantly better (P < 0.05) in those children without middle ear effusion. However, this group consisted of only 22 patients.

Casselbrant 1992 reported the rate of new episodes per arm was 1.08 in the placebo group versus 1.02 in the TT group (P = 0.25). In the placebo group, 40 percent had no further episodes of AOM, compared to 35 percent in the TT group. In addition, TT placement significantly decreased the percentage of time with AOM compared to placebo (P < 0.001).

Kujala 2012 reported failure rates (defined as at least two episodes of AOM in 2 months, three in 6 months or persistent effusion lasting at least 2 months), percent of children with no recurrent AOM, cumulative number of AOM episodes, and one-year incidence rates. There was an absolute difference in the proportion of failures of −13 percent (95% CI −25 to −01) between the TT and control groups, favoring TT. The one year incidence rate (infections per child per year) was 0.55 (95% CI 0.93 to 0.17) lower in the TT group compared to the control group.

TT Versus Antibiotic Prophylaxis In the Gonzalez 1986 RCT, 54.5 percent of children in the TT group and 24 percent in the

sulfisoxazole prophylaxis group had no recurrent AOM (P = 0.02). The attack rate was 0.86 infections per child in the TT group and 1.4 in prophylaxis group (P = 0.08).

Casselbrant 1992 reported a rate of 0.6 episodes of recurrent AOM per child-year children treated with Amoxicillin and a rate of 1.02 in their TT group (P = 0.001).

El-Sayed found no difference in the treatment outcomes of children treated with trimethoprim/sulfamethoxazole compared to children treated with TT (P = 0.37).

TT Versus TT and Adenoidectomy An RCT by Mattila 2003 found no difference in cumulative hazard of recurrent AOM or in

efficacy, defined as one minus the adjusted relative risk in randomized and nonrandomized comparisons of children who underwent TT with adenoidectomy compared with TT alone.

In the Kujala 2012 study, there was no significant difference in the TT with adenoidectomy group compared to the TT only group in the number of failures (absolute difference −5%, 95% CI −16 to 6, P = 0.37), in the time to failure (P = 0.29) or to the first AOM (P = 0.6), or in the proportion of children with no AOM episodes (absolute difference 1%, CI −13 to 15, P =1.0).

A subsequent 2005 RCT, which enrolled 217 children, 162 of whom had recurrent AOM, again found no differences in the mean number of otitis media episodes overall or in the subgroup of children with recurrent AOM at enrollment.

Quality of Life Outcomes Although Kujala 2014 found that insertion of TT tubes, with or without adenoidectomy,

significantly reduced the risk of recurrent AOM, a subsequent publication from the same trial examining quality of life outcomes at study entry, 4 months and 12 months found no differences in overall ear-related quality of life (Otitis Media-6 questionnaire [OM-6]), or for the subscales of caregiver concern, emotional distress, physical suffering, activity limitations, hearing loss, or speech impairment between surgically treated and no surgery groups.

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Nonrandomized Comparative Studies In a cross-sectional study, Grindler 2014 reported both disease-specific quality of life

outcomes, utilizing OM-6 score, and health related quality of life, using the PedsWL Infant Impact Module, in 1208 patients. The OM-6 score was higher (reflecting worse otitis specific quality of life) in children in otolaryngology practices who had been recommended to undergo TT placement than in children with prior TT placement.

Key Question 2a There are no prospective planned comparisons evaluating whether the presence of middle ear

effusion (at time of surgical evaluation) modifies the effectiveness of TT placement for recurrent AOM. Gonzalez 1986 report a retrospective subgroup comparison based on the presence or absence of middle ear effusion at initial evaluation and conclude that the attack rate, as well as the number of patients who had no further bouts of AOM, was significantly better (p < 0.05) in those children without middle ear effusion. However, this group consisted of only 22 patients. Two studies specifically excluded patients with middle ear effusion at time of surgical evaluation.

Casselbrant 1992 analyzed data with a multivariable Poisson model, and concluded that TT reduced the number of episodes of AOM/otorrhea only in those subjects whose episodes of AOM occurred year round. In their model, younger age and white race were significantly associated with higher rates of recurrent AOM, but there treatment by age and treatment by race interactions were not found.

Key Question 3 We extracted data on the occurrence of 11 adverse events from 85 cohorts and from RCTs

and NRCSs included in KQs 1 and 2. The adverse events considered were: perioperative complications, otorrhea, tube blockage, granulation tissue formation, premature extrusion, displacement of the TT into the middle ear space, persistent perforation, myringosclerosis (tympanosclerosis), presence of atrophy, atelectasis or retraction, cholesteatoma and long term hearing loss. We did not consider other adverse events, such as antibiotic resistance, gastrointestinal side effects of antibiotics or pain related to ear drops. The number of publications reporting each event, and the median (with 25th and 75th percentiles) percent of patients and ears are summarized in Table C.

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Table C. Median percentage of patients and ears with adverse events associated with TT placement

Adverse Event N Publications

Patients: Median Percent [25%, 75th%]

Ears: Median Percent (25%, 75th%)

Perioperative Complications 4 NA NA Otorrhea 39 20.6 [13.1, 47.3] 10.4 [9.1, 28.2] Tube Blockage 18 9.0 [ 2.6, 10.7] 4.0 [2.8, 17.1] Granulation Tissue 12 3.3 [ 2.9, 5.7] 3.9 [1.8, 5.7] Premature Extrusion 18 13.3 [ 7.1,47.9] 4.1 [1.6, 14.0] TT Displacement into middle ear 8 NA 0.8 [0.7, 0.9]

Persistent Perforation 48 2.7 [1.8, 6.7] 2.9 [ 2.0, 5.3 ] Myringosclerosis 22 33.5 [5.0, 38.0] 17.1 [6.8, 43.9] Atrophy, Atelectasis or Retraction 22 13.9 [7.5, 25.9] 14.4 [ 5.0, 32.8] Cholesteatoma 24 0.9 [0.2, 1.8] 0.7 [ 0.1 ,3.2 ] Hearing Loss 10 8.0 [ 1.2, 19.2] NA

NA: Not calculated when number of patients (ears) < 5; TT=Tympanosotomy Tubes

See Appendix G of the full report for adverse event details by study, and for study specific details, including design, recruitment period, tube type(s) used, age, proportion with recurrent AOM, followup time, and study specific definitions. In general, the study specific definitions of adverse events are poorly reported and/or highly variable between studies.

Key Question 4 We identified 11 publications which reported 2 RCTs and 9 NRCSs, which evaluate a range

of interventions, from complete water restriction (e.g., no swimming or head immersion while bathing), physical protection while swimming (utilizing ear plugs or bathing caps), postexposure prophylactic ear drops, avoidance of high risk activities (e.g., diving), to completely unrestricted exposure to water. All studies compared either no-swimming or ear plugs with a second group of swimmers with or without post-exposure antibiotic ear drops.

In the two RCTs, Goldstein 2005 reported a slightly higher average rate of otorrhea per

month in children who did not wear ear plugs (mean 0.10 episodes/month, compared to a mean of 0.07; P = 0.05) in a Poisson regression model adjusting for compliance. Parker 1994 reported identical mean otorrhea rates in nonswimmers and swimmers. Table D summarizes the occurrence of one or more episodes of otorrhea in the RCTs.

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Table D. RCTs: Water precautions—one or more episodes of otorrhea Study PMID Enrollment dates Country (Design)

Followup time Intervention Population n/N (%) Odds ratio (95% CI)

Goldstein 2005 15689760

7/1996-6/1999 U.S.

1 year Ear plugs All Participants

42/90 (46.7) 0.68 (0.37 – 1.25)

No precautions All Participants

46/82 (56.1) [reference]

Ear plugs Children who each had ≥ 125 instances of water exposure

29/39 (74.3) 2.69 (0.95 – 7.64)

No precautions Children who each had ≥ 125 instances of water exposure

14/27 (51.8) [reference]

Parker 1994 8024107 12/1989-2/1991 U.S.

1 year Nonswimming All Participants

18/30 (60.0) 0.71 (0.29 – 1.76)

Ear plugs† All Participants

13/15 (86.7) 3.10 (0.64 – 15.04)

No precautions All Participants

42/62 (67.7) [reference]

†Randomized to the nonswimming group, but self-selected to swim using ear precautions (e.g., ear plugs, wax, cotton with petroleum jelly) – considered an NRCS in the meta-analysis.

RCT=Randomized Control Trial; NRCS=Nonrandomized Comparative Trial; CI=Confidence Interval

The forest plot in Figure I, summarizes the results of a random effects meta-analysis from the

NRCSs only with separate summary estimates for ear plugs and avoidance of swimming. The summary odds ratio comparing ear plugs versus no precautions of having one or more episodes of otorrhea was 1.70 (95% CI 0.95 to 3.06). The odds ratio for nonswimming compared to no precautions was 1.52 (95% CI 0.71 to 3.25). It is notable that events rates in the RCTs are systematically higher in both control and intervention arms in the RCTs compared with event rates in NRCSs. A possible explanation is more complete ascertainment of outcomes in RCTs.

There appears to be a statistically nonsignificant trend in the NRCSs, which favor no ear plugs and no precautions. This trend may reflect a possible bias (e.g. patients who chose to swim may be less likely to report minor degrees of otorrhea).

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Figure I. Nonrandomized comparative studies only, children with one or more episodes of otorrhea

CI= Confidence Interval; NRCS= Nonrandomized Comparative Study; OR = Odds ratio (values > 1 favor ‘no precautions’ arms; values < 1 favor intervention (ear plugs or nonswimming)

Overall, aside from the small reduction in mean number of episodes of otorrhea found in the

Goldstein RCT, the available evidence does not support the conclusion that either ear plugs or avoidance of swimming reduces the risk of otorrhea related to swimming.

Key Question 5 We identified 12 papers, representing 11 studies, reporting 10 RCTs and 1 NRCS, with a

total of 1811 patients analyzed (1405 in RCTs and 406 in NRCSs) that assessed the effectiveness of various interventions to treat TT otorrhea. The studies reported multiple comparisons, including oral antibiotics (amoxicillin and amoxicillin/clavulanate), various antibiotic drops and antibiotic-glucocorticoid drops, oral corticosteroids, and combinations. Several studies had a watchful waiting or placebo arm.

Two studies were excluded from our meta-analysis, the NRCS by Dohar where specific treatments used in the historical practice group and concurrent practice group were not reported and a study which compared an antibiotic-glucocorticoid topical drop containing neomycin sulfate, polymyxin B sulfate and hydrocortisone with a topical spray formulation containing neomycin sulfate and dexamethasone. The network of available comparisons is shown in Figure J.

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Figure J. Network of treatment comparisons (RCTs)

Topical Antibiotic-Glucocorticoid

Topical Antibiotic

PO Antibiotic

Oral Antibiotic & PO Glucocorticoid Watchful Waiting or Placebo

1 2 1

1

2

1 3

2

RCT= Randomized Control Trial; PO=Oral The network plot consists of nodes representing the interventions being compared and edges representing the available direct comparisons. The number of studies that include each comparison is indicated next to each edge (connecting lines with thickness proportional to this number).

Outcomes

Clinical Cure Eleven studies reported the number of clinically cured patients in each arm, often at multiple

time points. All studies reported additional intermediate outcomes (e.g., cessation, improvement or duration of otorrhea).

After excluding 4 studies, 7 studies were included in the network meta-analysis. We chose the time designated by each study as the test of cure (range 7 to 20 days after initiation of treatment). As shown in Table E, treatment strategies that include topical antibiotic drops predominate over both oral antibiotics and watchful waiting or placebo.

Table E. Probabilities (percent) that an intervention is among the three most effective with respect to clinical resolution of otorrhea

Intervention 1st 2nd 3rd 4th Topical Antibiotic-

Glucocorticoid 77 21 1 0

Topical Antibiotic 22 73 5 1 Oral antibiotic 1 5 83 12 Watchful waiting/placebo 0 1 12 87

Topical Antibiotic-Glucocorticoid & PO Antibiotic

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The plots show that topical antibiotic-glucocorticoid and antibiotic-only drops are superior to watchful waiting (Figure K).

Figure K. Relative effectiveness of interventions compared to watchful waiting or placebo

therapy

OR=Odds Ratio, CrI=Credible Interval

When compared to oral antibiotics, topical antibiotic-glucocorticoid drops are superior to oral antibiotics and there is a suggestion that topical antibiotic drops are also superior, although the credible interval overlaps the null effect (Figure L).

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Figure L. Relative effectiveness of interventions compared to treatment with oral antibiotics

OR=Odds Ratio, CrI=Credible Interval

Quality of Life Van Dongen 2014 was the only study to report quality of life outcomes. They evaluated

quality of life in 230 children with otorrhea who received watchful waiting, oral antibiotics, or antibiotic- glucocorticoid drops for 7 days. At baseline, the generic and disease-specific health-related quality-of-life scores indicated good quality of life and were similar across the groups. At 2 weeks of follow-up, the change in the generic health-related quality-of-life scores did not differ significantly among the study groups. The changes in the disease-specific health-related quality-of-life scores at 2 weeks were small but consistently favored eardrops. Confidence intervals were relatively wide.

Discussion

Overall Summary and Strength of Evidence Our systematic review of 172 publications focused on five Key Questions (KQ), which

evaluate the evidence for effectiveness of TT in children with chronic middle ear effusion and recurrent acute otitis media, the adverse events (harms) associated with this procedure, the need for water precautions in children with TT, and the treatment of TT otorrhea. Table E summarizes our dispositions about the strength of the evidence.

Key Question 1 In children with chronic otitis media with effusion, 54 publications reported results of 29

RCTs.

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Risk of bias for evaluation of hearing and middle ear effusion outcomes was rated as moderate to high. Limited information on quality of life and other patient-centered outcomes (cognitive, language, and behavioral) suggests that effects for these outcomes varied in magnitude and direction, even across subscales of the same test, and were not significantly different across the compared interventions. Risk of bias for quality of life outcomes as rated as low to moderate. Risk of bias for various outcomes in high risk populations was rated as high.

TT placement (compared to watchful waiting) resulted in improved average hearing thresholds 1 to 3 months after surgery (a period when the majority of tubes are functioning). Mean hearing thresholds after TT placement with or without adenoidectomy improved by approximately 10 dB when assessed at 1 to 3 months.

By 1 to 2 years, when most tubes have extruded, hearing thresholds are no longer different, reflecting the favorable natural history of spontaneous resolution of middle ear effusion in most children. There was a trend suggesting improved thresholds in children undergoing adenoidectomy, but credible intervals (CrI) are wide and include the null effect. The individual patient data meta-analysis (IPD) by Boonacker et. al., which relied on a composite outcome, concluded that adenoidectomy is most beneficial in children four years or older with persistent otitis media with effusion. In this group at 12 months, 51 percent of those who had adenoidectomy failed whereas 70 percent of those who did not have adenoidectomy failed (Risk Difference 19%: 95% Crl 12% - 26%; NNT (Number Needed to Treat) = 6). No significant benefit of adenoidectomy was found in children less than 4 years old.3

Data were very sparse with respect to which factors might predict those children more likely to benefit from TT. The individual patient data (IPD) meta-analysis reported by Rovers et al. focused on interactions between treatment and baseline characteristics. They found significant interactions between daycare attendance in children 3 years or younger, and in children over 4 years of age with a hearing level of 25 dB or greater in both ears, and concluded that TT might be used in young children attending day-care; or in older children with a hearing level of 25 dB or baseline hearing level persisting for at least 12 weeks. They noted that average hearing level at baseline did not obviously modify the effect estimate.16

There is limited evidence regarding quality of life outcomes, but neither of the two studies that evaluated parental stress and health related quality of life found significant improvements in surgically treated children. Evidence for improved cognitive, language, or behavioral outcomes after TT, compared to watchful waiting, is similarly lacking.

Key Question 2 In children with recurrent acute otitis media, seven publications reported results of six RCTs.

We were unable to provide pooled results due to the small number of studies, multiple interventions, and heterogeneity in reported outcomes. The limited available evidence suggests that TT placement decreases the number of further episodes and the overall number of episodes of recurrent AOM. Three RCTs consistently found no difference in recurrent episodes of AOM when comparing TT versus TT and adenoidectomy.

Very little evidence from RCTs is available to evaluate factors that identify children most likely to benefit from TT placement. Only one study addressed any predisposing factors. A post hoc subgroup (n=22) comparison in one study concluded that patients with middle ear effusion at the time of surgical evaluation had improved outcomes.17 Risk of bias across outcomes ranged from moderate to high.

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Key Question 3 In general, the study specific definitions of adverse events were poorly reported and/or highly

variable between studies. Not all cohorts followed all patients until extrusion of the tube, nor was followup complete in all studies. Several adverse event categories have very wide interquartile ranges (e.g. otorrhea, premature extrusion, and myringosclerosis). This is likely due to highly variable definitions. For example, in some studies counts of patients with at least one episode of otorrhea were included, while other studies included only patients with purulent ear discharge. Otorrhea is particularly complex to characterize, as it may with respect to frequency, duration, volume, character, and associated symptoms. Other adverse events, such as hearing loss and cholesteatoma, are likely confounded by the severity of preexisting and ongoing middle ear disease.

Key Question 4 We identified nine studies, two RCTs and seven NRCSs that evaluated physical ear

protection (e.g. ear plugs) or water restriction (e.g. no swimming or head immersion while bathing) in children after TT placement. One RCT reported a slightly higher average rate of otorrhea (after adjusting for compliance) in children who did not wear ear plugs.18 A second RCT, with high risk of bias, found a statistically nonsignificant difference in the odds ratio in nonswimmers versus swimmers.19 A meta-analysis of NRCSs with evaluated ear protection and nonswimming tended to favor no precautions and swimming, but these RCTs are subject to high risk of bias and the analysis did not exclude a null effect. For the comparison of ear plugs vs. no precautions, risk of bias was rated as moderate. For those comparisons and outcomes where the evidence consists of nonrandomized comparative studies only, risk of bias was rated as high.

Key Question 5 Seven RCTs were included in a network meta-analysis of the comparative effectiveness of

various treatments for TT otorrhea. Seven studies were included in a network meta-analysis of the comparative effectiveness of

various treatments for TT otorrhea. The common outcome evaluated was clinical cure, defined as absence of otorrhea after completion of treatment.

The odds of clinical cure were 12-fold (95% CrI: 1.9 – 82) higher [NNT 2.2 (assuming a baseline rate 0.45)]a for antibiotic-glucocorticoid drops, compared to watchful waiting/placebo. Similarly, the odds of clinical cure were 7.3-fold (95% CrI: 1.2 – 51) higher [NNT 2.5 (assuming a baseline rate of 0.45)]b for topical antibiotic drops (compared to watchful waiting/placebo).

Compared to oral antibiotics, treatment with topical-glucocorticoid drops demonstrated higher effectiveness, odds ratio 5.3 (95% CrI: 1.2 to 27) [NNT 3.2 (assuming a baseline rate 0.56)].c The odds ratio for topical antibiotic drops was 3.3 (95% CrI: 0.74 – 16)[NNT 5 (assuming a baseline rate of 0.69)]d, although the credible interval includes 1. Risk of bias was low for random sequence generation and allocation concealment. However, 8 of 10 studies had high risk of bias due to open label design, which precluded blinding of personnel and care providers. Risk of bias was rated moderate overall.

a As seen in: van Dongen TM, van der Heijden GJ, Venekamp RP, et al. A trial of treatment for acute otorrhea in children with tympanostomy tubes. N Engl J Med. 2014 Feb 20;370(8):723-33. doi: 10.1056/NEJMoa1301630. PMID: 24552319. (34 of 75 in watchful waiting arm)

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b As seen in: Heslop A, Lildholdt T, Gammelgaard N, et al. Topical ciprofloxacin is superior to topical saline and systemic antibiotics in the treatment of tympanostomy tube otorrhea in children: the results of a randomized clinical trial. Laryngoscope. 2010 Dec;120(12):2516-20. doi: 10.1002/lary.21015. PMID: 20979100. (12/26 cured in saline rinse (placebo) arm) c As seen in: van Dongen TM, van der Heijden GJ, Venekamp RP, et al. A trial of treatment for acute otorrhea in children with tympanostomy tubes. N Engl J Med. 2014 Feb 20;370(8):723-33. doi: 10.1056/NEJMoa1301630. PMID: 24552319. (43 of 77 cured in oral antibiotic arm) d As seen in: Goldblatt EL, Dohar J, Nozza RJ, et al. Topical ofloxacin versus systemic amoxicillin/clavulanate in purulent otorrhea in children with tympanostomy tubes. Int J Pediatr Otorhinolaryngol. 1998 Nov 15;46(1-2):91-101. PMID: 10190709. (101 of 146 cured in oral antibiotic arm)

An overall summary of main conclusions with an assessment of the strength of evidence is

summarized in Table F.

Table F. Summary of conclusions and associated strength of evidence dispositions Conclusion Strength of Evidence Comments Key Question 1- effectiveness of TT in children with chronic otitis media with effusion

Treatment with TT results in short term improvements in hearing thresholds, compared to Watchful waiting Improvements in hearing thresholds are not sustained at 12 to 24 months. Concurrent Adenoidectomy with TT is associated with longer term improvements in hearing thresholds

Moderate Moderate Low

Network metaanlysis -9.1 (CrI: -14.5, -3.2) dB at 1 to 3 months Network meta-analysis 0.03 (CrI: -3.9, 3.3) dB at 12 to 24 months Network meta-analysis -3.8 (CrI: -8.5, 0.62) at 12-24 months (92% probability one of 3 most effective interventions)

Periods of watchful waiting do not result in consistently worse cognitive, language, behavioral or quality of life outcomes in children without comorbidities.

Low Limited number of studies (8), each using different outcome definitions No quantitative synthesis done

Key Question 2 - Comparative effectiveness of TT in recurrent acute otitis media

Treatment with TT does not improve quality of life Low Limited number of RCTs (1) No quantitative synthesis done

Key Question 4 – Effectiveness of ear plugs or avoidance of swimming

Ear plugs or avoidance of swimming does not reduce the risk of otorrhea after swimming

Low Limited number of studies (2 RCTs) Meta-analysis of 7 NRCSs

Key Question 5 – Effectiveness of topical antibiotic drops vs. systemic antibiotics or watchful waiting

Topical antibiotic-glucocorticoid drops are superior to oral antibiotics in achieving clinical cure Topical antibiotic drops are superior to oral antibiotics in achieving clinical cure

Moderate Low

Network meta-analysis OR: 5.3 (CrI: 1.2, 27.0) Network meta-analysis OR: 3.3 (CrI: 0.75, 16.0) (95% probability one of 2 most effective interventions)

Topical antibiotic-glucocorticoid drops and topical antibiotic drops are both superior to Watchful waiting in achieving clinical cure of otorrhea

Moderate Network meta-analysis OR: 12.0 (CrI: 1.9, 82) [antibiotic-glucocorticoid] OR: 7.2 (CrI: 1.2, 51.0) [antibiotic only]

CrI = credible interval; OR = odds ratio; TT=Tympanostomy Tubes; NRCS=Nonrandomized Comparative Study; RCT=Randomized Control Trial

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Limitations The available evidence base is composed of studies that evaluate multiple interventions.

Several of these (e.g. myringotomy alone and oral antibiotic prophylaxis) are rarely used in current practice. Thus, the direct evidence relating to the comparisons of interest relies on a smaller subset of studies or must be augmented with indirect evidence from network meta-analysis. Many of these trials were performed prior to widespread use of conjugate pneumococcal vaccines and in an era where antibiotic resistance was less common. It is unclear whether these or other factors affect the relative (current vs. historical) benefits of TT placement for recurrent AOM.

The majority of trials utilized similar inclusion criteria and subgroup analysis of higher or lower risk groups is sparse. The generalizability of results to infants and young toddlers and to school age children is also uncertain, given that children in these age groups are underrepresented in available trials. With the exception of two older trials that included children with chronic middle ear effusion (MEE) and/or recurrent AOM, most enrolled predominately children with chronic MEE. The degree to which patients in clinical practice may have both chronic MEE and recurrent AOM is unclear.

Reporting of possible sociodemographic risk factors is sparse and inconsistent, which limits the ability to draw conclusion about which of these factors might influence the relative effectiveness of TT.

With the exception of a few NRCSs, patients with cleft palate and Down syndrome have been systematically excluded from comparative trials, limiting the applicability of the evidence to these and other small subgroups, who experience a higher burden of middle ear disease. Similarly, patients at increased risk of developmental or behavioral sequelae from middle ear disease are not included (or at least identified) in trials to date.

Across RCTs relative to KQs 1 and 2, there was universal lack of blinding of participants and, in many cases, of outcome assessors. Given the intervention in question, placement of a tube in a visible anatomic structure, blinding of participants is not easily accomplished. In addition, many studies are at risk for attrition bias due to dropouts and incomplete followup.

Our meta-analysis of hearing levels used average pure tone hearing levels (typically reported as an average over frequencies of 500, 1000, 2000 and 4000 Hz). This simple measurement is likely insufficient to fully elucidate the complex relationships between hearing and speech perception and development in children.

Assessment of the effectiveness of TT in children with recurrent acute otitis media is particularly challenging, since an episode of AOM in control children (with intact tympanic membrane) results in otalgia and inflammatory changes, whereas children with a functioning TT may present with varying degrees of otorrhea. Bacterial cultures performed in the setting of research may assist in differentiating infections due to organisms associated with AOM from superinfections or colonization with other organisms (e.g. Staphylococcus or Pseudomonas species). Intermediate outcomes, which rely on simple counts or rates of otorrhea, fail to account for the variable nature of otorrhea with respect to duration, character, and patient impact.

Our network meta-analysis of the effectiveness of treatments for otorrhea combines trials of fluoroquinolones with other non FDA approved preparations. This presumes equivalent effectiveness and does not consider variable side effects such as ototoxicity, which may be associated with some agents.

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Future Research Recommendations Current indications for TT placement largely reflect the inclusion criteria used in clinical

trials. Prognostic models are urgently needed to stratify children with regard to their risk of persistence of middle ear effusion or recurrent AOM.

Pragmatic trials are needed, particularly in children with recurrent AOM, but also in children with chronic MEE and children with risk factors, such as cleft palate or Down syndrome. If possible, trials should be powered with planned subgroup analyses in groups at higher versus lower risk of outcomes.

Since TT are no longer effective after extrusion, future trials should record per-ear and per-patient outcomes that are conditional on whether the TT has extruded. Trialists should explore methods to control for high rates of potential cross-over from watchful waiting to surgical intervention.

Outcome assessment in children with recurrent acute otitis media is challenging, since an episode of AOM in children with an intact tympanic membrane results in otalgia and inflammatory changes, whereas children with a functioning TT exhibit otorrhea. Reliance on outcomes based on simple counts or rates of otorrhea fail to account for the variable character of otorrhea, which can be transient (of little to no concern), recurrent (of more concern, but usually readily managed), or chronic (of considerable concern and difficult to manage). Future trials would benefit from standardization and consistent definition of adverse events. In some cases, e.g. premature extrusion, one author’s premature extrusion may be another’s time extrusion, depending on the duration of anticipated need.20

Bacteriologic evaluations performed in the research setting may assist in differentiating otorrhea resulting from infection with organisms associated with AOM (e.g. Streptoccus pneumoniae, nontypable Haemophilus influenza)from superinfections with organisms associated with chronic otorrhea (e.g. Staphylococcus aureus and Pseudomonas aeruginosa).21

Conclusions Overall, the evidence suggests that TT placed in children with persistent middle-ear effusion

result in short term improvements in hearing compared to watchful waiting. However, there is no evidence of a sustained benefit.

Our network meta-analysis of hearing thresholds suggests the possibility of a more sustained improvement in hearing thresholds in at least some children who undergo adenoidectomy and TT placement. However, a nuanced understanding of which children may benefit from adenoidectomy is limited by the small evidence base and our use of aggregate data.

The evidence suggests that a period of watchful waiting does not worsen language, cognition, behavior, or quality of life. However, the current evidence base provides little guidance for the treatment of children who may be at increased risk for speech, language, or learning problems because of baseline sensory, physical, cognitive or behavioral factors.

Children with recurrent AOM may have fewer episodes after TT placement, but the evidence base is severely limited. It is unclear that quality of life outcomes are improved. The benefits of TT placement must be weighed against a variety of adverse events associated with TT placement.

In children in whom TT have been placed, there is no compelling evidence for the need to either avoid swimming or bathing or use ear plugs or bathing caps

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Should otorrhea develop, the available evidence supports topical treatment of TT otorrhea.

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References 1. Rosenfeld RM, Schwartz SR, Pynnonen MA,

et al. Clinical practice guideline: Tympanostomy tubes in children. Otolaryngol Head Neck Surg. 2013 Jul;149(1 Suppl):S1-35. doi: 10.1177/0194599813487302. PMID: 23818543.

2. Schilder AG, Chonmaitree T, Cripps AW, et al. Otitis media. Nat Rev Dis Primers. 2016;2:16063. doi: 10.1038/nrdp.2016.63. PMID: 27604644.

3. Boonacker CW, Rovers MM, Browning GG, et al. Adenoidectomy with or without grommets for children with otitis media: an individual patient data meta-analysis. Health Technol Assess. 2014 Jan;18(5):1-118. doi: 10.3310/hta18050. PMID: 24438691.

4. Grindler DJ, Blank SJ, Schulz KA, et al. Impact of Otitis Media Severity on Children's Quality of Life. Otolaryngol Head Neck Surg. 2014 Mar 13;151(2):333-40. doi: 10.1177/0194599814525576. PMID: 24627408.

5. Rosenfeld RM, Jang DW, Tarashansky K. Tympanostomy tube outcomes in children at-risk and not at-risk for developmental delays. Int J Pediatr Otorhinolaryngol. 2011 Feb;75(2):190-5. doi: 10.1016/j.ijporl.2010.10.032. PMID: 21106257.

6. Rettig E, Tunkel DE. Contemporary concepts in management of acute otitis media in children. Otolaryngol Clin North Am. 2014 Oct;47(5):651-72. doi: 10.1016/j.otc.2014.06.006. PMID: 25213276.

7. Cullen KA, Hall MJ, Golosinskiy A. Ambulatory surgery in the United States, 2006. Natl Health Stat Report. 2009 Jan 28(11):1-25. PMID: 19294964.

8. Proceedings from the National Summit on Overuse. 2012. The Joint Commission. https://www.jointcommission.org/assets/1/6/ National_Summit_Overuse.pdf. Accessed December 21, 2016.

9. Hoffman HJ, Daly KA, Bainbridge KE, et al. Panel 1: Epidemiology, natural history, and risk factors. Otolaryngol Head Neck Surg. 2013 Apr;148(4 Suppl):E1-E25. doi: 10.1177/0194599812460984. PMID: 23536527.

10. Casselbrant ML, Kaleida PH, Rockette HE, et al. In reference to What is the role of tympanostomy tubes in the treatment of recurrent acute otitis media? Laryngoscope. 2013 Dec;123(12):E127. doi: 10.1002/lary.24142. PMID: 24105683.

11. van Dongen TM, Schilder AG, Venekamp RP, et al. Cost-effectiveness of treatment of acute otorrhea in children with tympanostomy tubes. Pediatrics. 2015 May;135(5):e1182-9. doi: 10.1542/peds.2014-3141. PMID: 25896832.

12. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. AHRQ Publication No. 10(12)-EHC063-EF. Rockville, MD: Agency for Healthcare Research and Quality. April 2012.

13. Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. doi: 10.1136/bmj.d5928. PMID: 22008217.

14. Wells GA SB, O’Connell D, Peterson J, Welch V, Losos M, Tugwell P. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses.

15. Berkman ND, Lohr KN, Ansari M, et al. AHRQ Methods for Effective Health Care: Grading the Strength of a Body of Evidence When Assessing Health Care Interventions for the Effective Health Care Program of the Agency for Healthcare Research and Quality: An Update. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. Rockville (MD): Agency for Healthcare Research and Quality (US); 2008.

16. Rovers MM, Black N, Browning GG, et al. Grommets in otitis media with effusion: an individual patient data meta-analysis. Arch Dis Child. 2005 May;90(5):480-5. doi: 10.1136/adc.2004.059444. PMID: 15851429.

17. Gonzalez C, Arnold JE, Woody EA, et al. Prevention of recurrent acute otitis media: chemoprophylaxis versus tympanostomy tubes. Laryngoscope. 1986 Dec;96(12):1330-4. PMID: 3537596.

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18. Goldstein NA, Mandel EM, Kurs-Lasky M, et al. Water precautions and tympanostomy tubes: a randomized, controlled trial. Laryngoscope. 2005 Feb;115(2):324-30. doi: 10.1097/01.mlg.0000154742.33067.fb. PMID: 15689760.

19. Parker GS, Tami TA, Maddox MR, et al. The effect of water exposure after tympanostomy tube insertion. Am J Otolaryngol. 1994 May-Jun;15(3):193-6. PMID: 8024107.

20. Kay DJ, Nelson M, Rosenfeld RM. Meta-analysis of tympanostomy tube sequelae. Otolaryngol Head Neck Surg. 2001 Apr;124(4):374-80. PMID: 11283489.

21. Idicula WK, Jurcisek JA, Cass ND, et al. Identification of biofilms in post-tympanostomy tube otorrhea. Laryngoscope. 2016 Aug;126(8):1946-51. doi: 10.1002/lary.25826. PMID: 27426942.

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Introduction Background and Objectives

Uncertainty about the effectiveness of tympanostomy tubes (TT) for children with otitis media, indications for tympanostomy in children, effectiveness of antibiotics for children with tube otorrhea, and the need for prophylactic water precaution devices prompted the Agency for Healthcare Research and Quality to commission a review of the evidence to help inform recommendations concerning surgical indications and management strategies for TT placement.

Otitis media is often preceded by a viral upper respiratory tract infection that causes Eustachian tube obstruction, negative middle ear pressure, and accumulation of fluid in this normally air-filled space. Acute otitis media (AOM) is defined as the presence of fluid in the middle ear with signs and symptoms of an acute infection, such as fever and ear pain. Otitis media with effusion (OME) is defined as the presence of fluid in the middle ear behind an intact tympanic membrane without signs and symptoms of an acute infection.1,2 OME is defined as chronic OME, if effusion persists for 3 months or longer.1 Acute otitis media and chronic OME have shared causes. Children with chronic OME are prone to recurrent AOM episodes, and after an AOM episode all children have OME for some time.3

Myringotomy with TT placement is the most common ambulatory surgery performed on children in the United States4, with 667,000 TT placed in children under the age of 15 in 2006.5

The proceedings of the National Summit on Overuse, convened in 2012, based on sample of continually enrolled children into a treatment pathways database and a Medicaid database, reported that 2.5 percent of all U.S. children 2 years old and older had TT inserted in 2010.6

A 1994 study reported indications for TT placement in children: 30 percent were for chronic OME, 24 percent for recurrent AOM, and 46 percent of surgical candidates had both recurrent AOM and chronic OME.7

Chronic OME can result in hearing deficits, which put a child at risk for speech and language delays, behavioral changes, and poor academic achievement. Recurrent AOM has been shown to impact quality of life for patients and their caregivers.8 The comparative effectiveness of TT for chronic OME and recurrent AOM is likely influenced by the many factors that affect the prognosis for middle ear disease in children, including current age, age at first diagnosis, frequency of respiratory tract infections, and day care exposure.9 Children with middle ear effusions that are bilateral and continuously present are likely at higher risk. Tube lifespan is likely to be an important mediator of effectiveness.

Because recurrent AOM and chronic OME have shared causes, and for many patients represent a continuum, it may be important to consider children’s risk of these conditions and risk of important outcomes under various treatments for these conditions when researching or planning a child’s optimal management. A risk-centered approach might involve differential management of children with otitis media by their risk of important outcomes, as obtained from risk prediction models, which may be preferable to algorithms that use a single threshold for duration or frequency of a diagnosis.10

Along these lines we note that certain children, including those with Down syndrome and cleft palate, have a very high risk for middle ear disease. In a retrospective review of patients with Down syndrome, the authors found that the majority of patients required two or more sets of tubes during their childhood.11 Due to the effects of palatal dysfunction on Eustachian tube function, children with cleft palate also have a high incidence of OME and associated hearing loss.12 The American Academy of Otolaryngology–Head and Neck Surgery (AAO-HNS) clinical practice guideline

1

(CPG) identifies a subpopulation of children who may be at increased risk for speech, language, or learning problems from otitis media because of baseline sensory, physical, cognitive, or behavioral factors.1 The inclination to treat OME more aggressively in these children is reflected in a study that found that approximately 1 in 6 children with autism spectrum disorder underwent TT placement.13

The AAO-HNS CPG concludes that the efficacy of TT for preventing recurrent AOM is unclear, with systematic reviews reporting insufficient evidence, small short-term benefits, or moderate benefits of similar magnitude to antibiotic prophylaxis. They note the overall favorable natural history of otitis media without persistent middle ear effusion.14 The AAO-HNS CPG recommends that clinicians should offer TT to children with recurrent AOM and middle ear effusions based on shared decisionmaking with the child’s caregiver. They conclude that there is no benefit if one considers only randomized controlled trials with AOM that clears between episodes (without chronic OME) and recommend that tubes not be placed in children with recurrent AOM who have a normal ear examination at the time of assessment for tube candidacy.1 The American Academy of Pediatrics CPG discourages routine use of prophylactic antibiotics to prevent recurrent AOM.15 The reluctance to use antibiotic prophylaxis because of concerns about antibiotic resistance may result in increased use of TT in children with recurrent AOM. Attempts to promote the use of more rigorous criteria for the diagnosis of AOM may also result in improved effectiveness of TT.

A 2014 review by Tsao and Goode provides a narrative summary of their search for evidence regarding water precautions to prevent post-TT otorrhea.16 They discuss systematic reviews published in 1999 and 2002 and a randomized controlled a trial published in 2005 and conclude that water precautions should not be routinely advised.

Acute otorrhea is common after TT placement.17 Postoperative otorrhea (up to 30 days after surgery) is common and reflects, in part, underlying (preoperative) middle ear glandular changes and inflammation. Some otorrhea is to be expected, since the role of the tube is to ventilate the middle ear. Episodes of otorrhea that reflect acute bacterial infection may be otherwise asymptomatic and less troublesome than AOM episodes in children with intact eardrums.18 However, otorrhea may be associated with a foul odor, fever, or pain, and may negatively affect quality of life. Treatment is aimed at eradicating bacterial infection and reducing the duration and severity of symptoms.19 A number of subgroups of acute otorrhea exist, including: 1) otorrhea in the immediate postoperative period, 2) otorrhea caused by the same pathogens as AOM, including Moraxella catarrhalis, Haemophilus influenzae, and Streptococcus pneumoniae, and 3) otorrhea resulting from superinfection with Staphylococcus aureus, including methicillin resistant Staphylococccus aureus (MRSA), and Pseudomonas associated with biofilms.20

The objectives for the systematic review are to synthesize information on the effectiveness of TT in children with chronic otitis media with effusion and recurrent acute otitis media, to summarize the frequency of adverse effects and/or complications associated with TT placement, to synthesize information on the necessity for water precautions in children with TT, and to assess the effectiveness of available treatments for otorrhea in children who have TT.

Key Questions With input from clinical experts during Topic Refinement, and from the Public, during a public

review period, we developed the following Key Questions and study eligibility criteria. Key Question 1: For children with chronic otitis media with effusion, what is

the effectiveness of TT, compared to watchful waiting, on

2

resolution of middle ear effusion, hearing and vestibular outcomes, quality of life, and other patient-centered outcomes? a) What factors (such as age, age of onset, duration of

effusion, comorbidities, and sociodemographic risk factors) predict which children are likely to benefit most from the intervention?

b) Does obtaining a hearing test help identify which children are more likely to benefit from the intervention?

Key Question 2: For children with recurrent acute otitis media, what is the

effectiveness of TT, compared to watchful waiting with episodic or prophylactic antibiotic therapy, on the frequency and severity of otitis media, quality of life, and other patient-centered outcomes? a) What factors (such as age, age of onset, number of

recurrences, presence of persistent middle ear effusion, comorbidities, sociodemographic risk factors, history of complications of acute otitis media, antibiotic allergy or intolerance) predict which children are likely to benefit from the intervention?

Key Question 3: What adverse events, surgical complications, and sequelae

are associated with inserting TT in children with either chronic otitis media with effusion or recurrent acute otitis media?

Key Question 4: Do water precautions reduce the incidence of TT otorrhea

or affect quality of life?

Key Question 5: In children with TT otorrhea, what is the comparative effectiveness of topical antibiotic drops versus systemic antibiotics or watchful waiting on duration of otorrhea, quality of life, or need for tube removal?

Analytic Frameworks The analytic frameworks in Figures 1 through 3 describe the specific linkages associating the

populations of interest, exposures, modifying factors, and outcomes of interest the assessment of studies that examine the association between TT placement and intermediate and final health outcomes and harms (KQs 1, 2 and 3; Figure 1), need for water precautions (KQ 4; Figure 2), and treatment of otorrhea (KQ 5; Figure 3).

3

Figure 1. TT in Children with chronic OME or recurrent AOM (Key Questions 1, 2, and 3)

OME=otitis media with effusion; AOM=acute otitis media; TT=tympanostomy tubes; KQ=Key Question Figure 2. Need for water precautions in children with TT (Key Question 4)

OME=otitis media with effusion; AOM=acute otitis media; TT=tympanostomy tubes; KQ=Key Question

Quality of life and patient-centered outcomes

Global and otitis-specific child andparental quality of life

Speech and language outcomes Educational achievement Behavioral outcomes

Adverse events

• Anesthetic and surgical• Otorrhea • Blockage of tube lumen• Granulation tissue• Premature extrusion• TT displacement into middle ear• Persistent perforation• Myringosclerosis• Atrophy, atelectasis or retraction• Worsened hearing thresholds

Tympanostomy tube placement(+/- adenoidectomy)

(KQ 3) Intermediate outcomes

Middle ear effusion prevalence (KQ 1) Recurrent AOM/otorrhea (KQ 2) Hearing and vestibular outcomes (KQ 1) Behavioral outcomes Antibiotic use Need for TT reinsertion

Children with chronic OME and/or

recurrent AOM

(KQ 1, KQ 2)

Modifiers of comparative effectiveness• Age, age of onset (KQ1a, KQ2a)

• Duration of middle ear effusion (KQ1, KQ2)

• Frequency of recurrent AOM (KQ 2a)

• Complications of AOM (KQ2)

• Antibiotic allergy or intolerance (KQ2)

• Hearing testing (KQ1b,)

• Comorbidities (KQ1a, KQ2a)

• Sociodemographic risk factors (KQ1a, KQ2a)

Water precautions

Children with chronic OME and/or

recurrent AOM

with

Tympanostomy tubes

Intermediate outcomes

Otorrhea, incidence and duration

Final health outcomes

Global and otitis-specific child and parental QoL

(KQ 4)

4

Figure 3. Treatment of otorrhea in children with TT (Key Question 5)

OME=otitis media with effusion; AOM=acute otitis media; TT=tympanostomy tubes; KQ=Key Question

Children with chronic OME and/or

recurrent AOM after TT placement

with

Otorrhea

Topical antibiotic drops

(Treatment)(KQ 5)

Intermediate outcomes

Duration of otorrhea Need for TT removal

Final health outcomes

Global and otitis-specific child and parental QoL

Adverse events

• Ototoxicity• Allergic reactions

5

Methods The Brown Evidence-based Practice Center (EPC) conducted this review based on a systematic

review of the published scientific literature using established methodologies as outlined in the Agency for Healthcare Research and Quality’s (AHRQ) Methods Guide for Effectiveness and Comparative Effectiveness Reviews.21 The PROSPERO protocol registration number is CRD42015029623.

Eligibility Criteria We use the Population, Intervention, Comparator, Outcomes, and Designs (PICOD) formalism

to define the characteristics of the eligible studies for this review.

Populations For all KQs, studies of children and adolescents from 1 month to 18 years old were eligible. We

defined five age groups, namely infants (28 days to 12 months), toddlers (13 months to 2 years), early childhood (2 to 5 years), middle childhood (6 to 11 years), and early adolescence (12 to 18 years).22 Subpopulations of interest included children at high risk of recurrent AOM or OME, such as children with Down syndrome, cleft palate, other craniofacial anomalies, or primary ciliary dyskinesia; and children at high risk of adverse clinical or developmental outcomes, such as those with preexisting hearing loss, speech and language problems, or various developmental disorders. We were also interested in the population of children who have sociodemographic risk factors (e.g. day care exposure or low socioeconomic status).

For Key Question (KQ) 1, we included studies of children with chronic OME. We preferred the standard definition of effusion that persists for at least 3 months,1 but also included results based on studies’ alternative definitions, if our preferred one was not reported. We excluded studies of children with chronic suppurative otitis media since it is associated with a persistently perforated tympanic membrane.

For KQ 2, we included children with recurrent AOM with or without middle ear effusion, defined as three or more well-documented and separate AOM episodes in the past 6 months or at least four well-documented and separate AOM episodes in the past 12 months with at least one in the past 6 months.23 For studies that did not report the preferred definition we recorded the study specific definition.

For KQ 3 and 4, we included studies in children with TT placed for OME or AOM. For KQ 5, we included studies of symptomatic or asymptomatic children with acute TT otorrhea beyond the immediate postoperative period. We defined the immediate postoperative period as 30 days after surgery, but included studies reporting results near that period (e.g., 28 days, 4 weeks).

Interventions/Exposures For KQs 1, 2, and 3 we considered all studies that included myringtomy with TT placement,

with or without adenoidectomy. Tubes were classified as short-term tubes (generally in place for 10-18 months) and long-term tubes (e.g. T-tubes, which typically remain in place for several years).

In KQ 4, we distinguished three categories of interventions; avoidance (e.g. of swimming or head immersion while bathing), canal occlusion methods (e.g. earplugs or headbands), and postexposure prophylaxis using ototopical antibiotics.

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In KQ 5 we compared ototopical preparations, including FDA approved products (i.e. ofloxacin otic 0.3%, ciprofloxacin 0.3% & dexamethasone 0.1%), and other non FDA-approved agents (e.g. hydrocortisone & bacitracin & colistin).

Comparators For KQ 1, comparisons of primary interest were watchful waiting or adenoidectomy.

Comparators for KQ2 included watchful waiting, with systemic or topical antibiotic therapy for recurrent episodes of AOM, prophylactic antibiotics and adenoidectomy. KQ 3 did not address comparative harms. In KQ 4, comparators included no water precautions with or without avoidance of higher risk activities (e.g. diving or underwater swimming and ear plugs or swimming caps). The primary comparators for KQ5 were watchful waiting and oral antibiotic therapy.

Outcomes For KQs 1 and 2, which address the effectiveness of TT, we considered intermediate

outcomes, including prevalence of middle ear effusion, measures of hearing and vestibular function, such as improved hearing thresholds (audibility), tests of auditory perception and discrimination (clarity), and balance and coordination (vestibular function). For KQ 2, measures of recurrent AOM, including otorrhea were also extracted.

Quality of life and patient-centered outcomes included global and otitis-specific child and parental quality of life, speech and language outcomes, educational achievement, and behavioral outcomes, such as disobedience, enuresis, or tantrums.

The following adverse event outcomes were extracted for KQ 3: Intraoperative and immediate postoperative anesthetic and surgical adverse events, otorrhea, blockage of the tube lumen, granulation tissue, premature extrusion, TT displacement into the middle ear, persistent perforation of the tympanic membrane, myringosclerosis, tympanic membrane atrophy, atelectasis and retraction pockets, worsened hearing thresholds, and other reported adverse events (plausibly related to TT). Studies reporting only postoperative otorrhea (during the 30 days after surgery )was excluded, as this outcome is likely confounded by the preoperative state of the middle ear.

Outcomes for KQ 4 (water precautions) included final health and patient-centered outcomes related to child and parental quality of life and intermediate outcomes related to the incidence and duration of otorrhea.

Outcomes evaluated relating to KQ 5 (treatment of otorrhea) included global and otitis-specific child and parental quality of life, duration of otorrhea, and need for removal of TT. Postoperative otorrhea was not an outcome of interest.

Timing We included studies with any duration of followup.

Setting Studies performed in both primary and specialty care settings were included.

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Study Design We evaluated published, peer-reviewed studies only. Conference abstracts were excluded. For

KQs 1 and 2, we included randomized comparative trials and nonrandomized comparative studies, prospective and retrospective, where treatment was assigned on a per patient basis. Studies with per ear assignment were excluded (e.g. TT placed by design in one ear only).

For KQ 3, we included prospective surgical studies enrolling at least 50 subjects (including arms of RCTs or NRCSs with 50 or more patients) and population based retrospective single-group studies (registry studies) with ≥1000 subjects.

Evidence Identification We conducted literature searches of all studies in MEDLINE®, both the Cochrane Central

Trials Registry and Cochrane Database of Systematic Reviews, EMBASE®, and CINAHL® (from inception) to identify primary research studies meeting our criteria. We used the search strategies in Appendix A. The last search was run on May 19, 2016. The TEP was asked to provide citations of potentially relevant articles. Additionally, we perused the reference lists of published clinical practice guidelines, relevant narrative and systematic reviews, and examined Scientific Information Packages from manufacturers. Existing systematic reviews were used primarily as sources of studies; we extracted and incorporated all studies de novo, and did not summarize or incorporate existing systematic reviews, per se.

We searched Devices@FDA.gov at www.accessdata.fda.gov/scripts/cdrh/devicesatfda/ for the classification product code “ETD” (TT). This returned 109 records, all of which are deemed to be substantially equivalent to previous devices (indicating there are no new data that the FDA considered) or have original approvals that predate the electronic records and require either contacting the manufacturer for information or requesting it from the FDA. We also searched the Clinicaltrials.gov Web site and the WHO International Clinical Trials Registry Platform for relevant study records. All records identified were screened for eligibility using the same criteria as was used for articles identified through literature searches.

At the start of citation screening, we implemented a training session, in which all researchers screened the same articles and conflicts were discussed. We iteratively continued training until agreement was reached regarding the nuances of the eligibility criteria for screening. All citations found by literature searches, including from sources other than electronic databases (e.g., TEP, existing systematic reviews) were independently screened by two researchers. Conflicts were resolved by discussion until a group consensus was reached. All screening was done in the open-source, online software Abstrackr (http://abstrackr.cebm.brown.edu/).

Data Extraction and Data Management Each study was extracted by one methodologist. The extractions were reviewed and confirmed

by at least one other methodologist. Any disagreements were resolved by discussion among the team members. Data was extracted into customized forms in the Systematic Review Data Repository (SRDR) online system (http://srdr.ahrq.gov). Upon completion of the review, the SRDR database will be made accessible to the general public with capacity to read, download, and comment on data. The basic elements and design of these forms is similar to those we have used for other comparative effectiveness reviews and includes elements that address population characteristics; descriptions of the interventions, exposures, and comparators analyzed; outcome

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definitions; effect modifiers; enrolled and analyzed sample sizes; study design features; funding source; results; and risk of bias questions.

Assessment of Methodological Risk of Bias of Individual Studies

We assessed the methodological quality of each study based on predefined criteria. For RCTs, we used the Cochrane risk of bias tool,24 which asks about risk of selection bias, performance bias, detection bias, attrition bias, reporting bias, and other potential biases. For observational studies, we used relevant questions from the Newcastle Ottawa Scale.25 The methodological attributes of studies and comments on study execution and outcome measurement that pertain to specific outcomes within a study were considered when determining the overall strength of evidence for conclusions related to those outcomes, as is standard practice.

Data Synthesis All included studies were summarized in narrative form and in summary tables that tabulate the

important features of the study populations, design, intervention, outcomes, and results. We analyzed different study designs separately. We compared and contrasted populations,

exposures, and results across study designs. We examined any differences in findings between observational and intervention studies. We evaluated the risk of bias factors as possible explanations for any heterogeneity.

Specific methods and metrics (summary measures) meta-analyzed were chosen based on available outcomes. We conducted quantitative analysis for outcomes that have at least five studies reporting results that could be combined in a meta-analysis. When available, these were summarized as odds ratios of categorical outcomes and net change of continuous outcomes (e.g., mean hearing threshold).

For KQ 4, we conducted direct pairwise random effects meta-analyses of nonrandomized comparative studies that were sufficiently similar in population, interventions (water restriction vs. ear protection), and outcomes. The two randomized comparative trials were not combined in a meta-analysis on the basis of clinical heterogeneity (suggestion of higher baseline risk), as well as methodological heterogeneity. Rather, each was individually reported. We used typical models that assume that study-specific latent treatment effects are normally distributed across studies,26 and estimated them by maximizing the restricted likelihood in a generalized linear mixed model, using the R27 package metafor.28

For KQs 1 and 5, we performed network meta-analysis of clinical outcomes to compare treatment alternatives. We conducted network meta-analyses in the Bayesian framework, using the R gemtc package.29, 30 A network meta-analysis is an extension of pairwise meta-analyses that simultaneously combines direct (when interventions are compared head-to-head) and indirect (when interventions are compared through other reference interventions) evidence. Combining the direct and indirect evidence not only improves precision of estimates, but also provides estimates for all pairwise comparisons, including those missing from the direct evidence. The key assumption of the network meta-analysis is that of consistency of direct and indirect effects. Consistency is likely to hold when the distribution of effect modifiers is (equivalently, patient characteristics are) similar across trials. If this assumption is violated, there may be inconsistency between the direct evidence and indirect evidence of treatment comparisons.

9

For network meta-analyses, we used a hierarchical model with a within-study level and a between-studies level that models responses at the arm level and nests arms within studies. We ran two sets of analyses, one assuming consistency of treatment effects and one examining this assumption. The models are shown in Appendix I. Briefly, the analysis assuming consistency parameterizes treatment effects as linear combinations of T-1 parameters, where T is the number of treatments in the network. Treatment effects are assumed to be normally distributed across studies with a common variance, i.e., are homoscedastic random effects. We used weakly informative default priors on study-level mean treatment effects and on between-study means and variances. Priors on the means were uniform distributions, with standard errors 15 times larger than the observed scatter of study effect estimates. We put uniform priors on the standard deviation of between-studies treatment effects, with support determined from the observed scatter of treatment effects.

Estimation was done with MCMC via the JAGS sampler,31 using initial values drawn randomly from the marginal distributions of the priors of respective parameters. We fit four MCMC chains. After a burn in of 5000 iterations, we monitored convergence of random effects means and variances automatically, by checking every 10000 iterations whether the Gelman Rubin diagnostic was less than 1.05 with 95% probability for all monitored parameters. After convergence was reached, an extra 10000 iterations were run. All models converged quickly, within 10000 iterations. Model fit was assessed by comparing the posterior mean of the residual deviance to the number of data points.32 The ratio of residual deviance to number of data points ranged from 0.97 to 1.06, suggesting adequate model fit.

For each analysis, we empirically assessed if the network meta-analysis consistency assumption was violated by comparing the direct and indirect evidence using a node-splitting approach. We separately parameterized the direct and indirect effects, and compared the estimates of the two.33, 34 These analyses were not suggestive of inconsistency, but in small networks, like the ones in this report, they can be underpowered. The split-node analysis is the statistically preferred version of naive analyses that compare direct and indirect estimates in a network. Formal model description, details of inconsistency analysis and illustrative trace and density plots are shown in Appendix I.

Results are presented in terms of means and corresponding 95% credible intervals (CrI). We also estimated the probability that a treatment is the most effective, second most effective, and so on, based on the results of the network meta-analyses. Statistical heterogeneity was explored qualitatively. Because of the relatively small number of studies, and the little variability in characteristics, meta-regression analyses were not performed. Instead, we did subgroup analyses for the study characteristics of interest described in the corresponding KQ. Because these subgroup analyses did not change conclusions, they are not reported in detail.

Grading the Strength of Evidence We graded the strength of evidence (SOE) as per the AHRQ methods guide on assessing the

strength of evidence.35 We assessed the strength of evidence for each outcome. Following the standard AHRQ approach, for each intervention and comparison of intervention and for each outcome, we assessed the number of studies, their study designs, the study limitations (i.e., risk of bias and overall methodological quality), the directness of the evidence to the KQs, the consistency of study results, the precision of any estimates of effect, the likelihood of reporting bias, and the

10

overall findings across studies. Based on these assessments, we assigned a strength of evidence rating as being either high, moderate, or low, or there being insufficient evidence to estimate an effect.

Assessing Applicability We assessed the direct applicability within and across studies with reference to children with

specific comorbidities (Down syndrome, cleft palate, etc.), and whether interventions and comparators are used in current practice.

11

Results

The literature searches yielded 13,334 citations (Figure 4). We identified 510 of these as potentially relevant full-text studies. These were retrieved for further evaluation. Overall, 339 full text articles did not meet eligibility criteria (see Appendix B for a list of rejected articles along with reasons for rejection); two additional publications were identified through a hand search of reference lists. . Searching the U.S. Food and Drug Administration (FDA) database, clinicaltrials.gov, and the WHO International Clinical Trials Registry Platform did not yield any trials with results that were not already included in the report.

A total of 173 articles are included in this report. Searching the FDA database, clinicaltrials.gov, and the WHO International Clinical Trials Registry Platform did not yield any trials with results that were not already included in the report.

As shown in Figure 4, the majority of included publications (n = 85) related to KQ 3. These included prospective surgical case series that followed 50 or more children after TT placement or large (≥ 1000 subject) registry-based retrospective cohorts. There are a relative paucity of studies available for the other the main effectiveness KQs.

12

Figure 4. Literature flow diagram

CINAHL = Cumulative Index to Nursing and Allied Health Literature; KQ = Key Question; NRCS = nonrandomized comparative trial; RCT = randomized controlled trial; some publications reported data from the same study. The KQ3 publications included 70 cohorts, 12 NRCSs and 3 RCTs from which the cohort most closely matching usual care was extracted. Detailed reasons for exclusion of studies reviewed in full text but not considered further are presented in Appendix B.

Key Question 1 For children with chronic otitis media with effusion, what is the effectiveness of tympanostomy tubes (TT), compared to watchful waiting, on resolution of middle ear effusion, hearing and vestibular outcomes, quality of life, and other patient-centered outcomes?

a) What factors (such as age, age of onset, duration of effusion, comorbidities, andsociodemographic risk factors) predict which children are likely to benefit most fromthe intervention?

b) Does obtaining a hearing test help identify which children are more likely to benefitfrom the intervention?

13

Eligible Studies We identified 54 publications. Of these, there were 29 papers reporting 16 RCTs.4, 36-63There were 24 publications reporting 24 NRCSs that assessed the effectiveness of TT in children with chronic middle ear effusion.64-87

Description of Randomized Trials Among the 16 RCTs (Table 1), a majority enrolled children in the preschool and early school

ages (mean age of enrolled children ranged from 1.6 to 5.4 years). Sample sizes ranged between 23 and 491. Most trials enrolled a majority of boys. The proportion of male children ranged from 48 to 82 percent. Most studies enrolled children with persistent middle ear effusion in one or both ears for periods of 2 to 6 months. Two studies included at least some patients with recurrent AOM with or without persistent middle ear effusion.36, 49 Most studies were conducted in the United States and Europe. The majority completed enrollment more than a decade ago. Reporting of age of onset, duration of effusion, and sociodemographic risk factors was sparse. All RCTs excluded children with major comorbidities (e.g. Down syndrome and cleft palate). For details, see Appendixes C-E.

As illustrated in Figure 5, and detailed in Table 1, the RCTs compare multiple interventions: TT, TT with adenoidectomy, myringotomy with adenoidectomy, myringtomy alone, adenoidectomy alone, oral corticosteroid treatment, antibiotic prophylaxis, and watchful waiting.

Figure 5. Evidence graph for the 16 RCTs

Evidence graph for the 16 RCTs (10 comparing pairs, 4 comparing triplets, and 2 comparing quadruplets of treatments) identified in the systematic review. Of the 28 possible comparisons that are possible, 16 were examined in the RCTs. The network plot consists of nodes representing the interventions being compared and edges representing the available direct comparisons. The number of studies that include each comparison is indicated next to each edge (connecting lines with thickness proportional to this number).

TT= tympanostomy tubes; RCTs= Randomized Control Trials

Adenoidectomy

Myringotomy & Adenoidectomy Prophylaxis

Oral Corticosteroid

Tympanostomy tubes

TT & Adenoidectomy TT ± Adenoidectomy

Watchful Waiting

Myringotomy

14

15

Table 1. Summary of randomized controlled trials (RCTs) Study Year PMID Country Inclusion Criteria Age (years) Enrollment

period Comparators (N) Hearing (measurement time in months)

MEE (followup in months)

Bernard 1991 1861917 Canada36

MEE > 3 months in at least one ear

2.5 to 7 NR Sulfisoxazole (65) vs. TT (60)

Mean HL (0,2,4,6,12,18)

NR

Casselbrant 2009 19819563 1997-2005 U.S.37

bilateral MEE >= 3 mo, unilateral MEE >= 6 mo

2.0 to 3.9 1997-2005

TT (32) vs. TT & adenoidectomy (32) vs Myringotomy & Adenoidectomy (34)

Study entry only Percent time with MEE (18, 36)

Chaudhuri 2006 23120310 India38

Unclear 0 to 12 NR Antibiotic prophylaxis (25) vs. Oral steroid (25) vs. Placebo (25) vs. TT +/- adenoidectomy (25)

Composite cure (appearance, audiometry, tympanography)

Gates 1987 3683478 U.S.88

suspected SOM with MEE persisting >= 2 months

4 to 8 4/1980-6/1984

TT (129) vs. Myringotomy (107) vs. vs. TT & Adenoidectomy (125) vs. Myringotomy & Adenoidectomy (130)

Time with abnormal hearing & time with HL >= 20 dB

Percent time with effusion & time to 1st recurrence, proportion of exams with effusion

Mandel 1989 2789777a U.S.44

MEE >= 2 mo 7 mo to 12 09/1979-09/1984

TT (30) vs. Myringotomy (29) vs Control (29)

HL (0, 1,2) Percent time with effusion (12, 24, 36)

Mandel 1989 2789777b U.S.44

MEE >= 2 mo 7 mo to 12 09/1979-09/1984

TT (11) vs. Myringotomy (12)

Mandel 1992 1565550 U.S.45

MEE >= 2 mo 7 mo to 12 11/1981-06/1987

TT (37) vs. Myringotomy (39) vs. Watchful waiting (4-6 months) (35)

HL (0,1,2,4) Percent time with effusion (12, 36)

Maw 1999 10459904 UK40, 46, 63

bilateral OME & HL > = 20 dB

NR 4/1991-12/1992

TT (92) vs. Watchful waiting (90)

HL (0, 9) Number with at least one middle ear without fluid

MRC Multicentre Otitis Media Study Group 2012 (TARGET) 12680834 UK 4, 47, 48

bilateral OME & better ear HL >= 20 dB for 3 mo

3.25 to 6.75 4/1994-1/1998

TT (126) vs. TT & adenoidectomy (128) vs. Watchful waiting (122)

HL (0,3,6,9,12,15,18,21,24)

Nguyen 2004 15126745 Canada49

recurrent OM with > 3 episodes in 6 mo or 4 in 12 mo,

1.5 to 18 01/1998-01/2003

TT (16) vs. TT & adenoidectomy (18)

Included in composite outcome

Included in composite outcome

16

persistent OME > 3 months, or HL > 30 dB

Paradise 2001 11309632 U.S.43, 50-52,

54

bilateral MEE >= 3 mo, unilateral MEE >= 135 days)

< 3 6/1991-12/1995

TT (216) vs. Watchful Waiting (213)

NR Percent time with effusion (6,12,18,24)

Popova 2010 20399511 Bulgaria55

bilateral MEE >= 3 mo & HL > 20 dB

3 to 7 2007-2009

TT (42) vs. Myringotomy AND Adenoidectomy (36)

HL (0,1,6,12) Number with recurrence

Rach 1991 2070526 Netherlands56

bilateral OME >= 6 mo

> 2 NR TT (22) vs. Watchful waiting (for 9 months then tubes if needed) (21)

NR NR

Rovers 2000 10969126 Netherlands41, 42, 57-60

bilateral persistent OME 4-6 months

> 9 mo 1/1996-4/1997

TT (93) vs. Watchful waiting (94)

HL (0,6,12) Percent with bilateral OME (3,6,9,12)

Velopic 2001 21397957 Croatia61

unilateral or bilateral OME >= 3 mo

2 to 12 2004- 2009

TT (56) vs. TT & adenoidectomy

Average and frequency specific air bone gap

(0, 6+)

Resolution of effusion at 6+ months postoperative.

Vlastos 2011 21205368 Greece62

sleep-disordered breathing & bilateral OME

3 to 7 5/2007-5/2008

TT & Adenoidectomy (25) vs. Myringotomy & Adenoidectomy (27)

HL (0,6,12)

TT: Tympanostomy tubes, HL: Hearing thresholds (time in months), OME: Otitis Media with effusion, MEE: Middle ear effusion, NR: not reported, mo: months

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Risk of Bias: RCTs Overall, RCTs that compared TT and nonsurgical arms had high risk of bias, due to lack of

blinding of participants and care providers (blinding is not feasible given the intervention). With the exception of Maw 199946 and Gates 1987,88 trials had unclear (did not report) or had high risk of bias for lack of blinding of outcome assessors. The details of random sequence generation were unclear in the majority of studies (unclear risk of bias). Randomization sequence generation was adequately described in four RCTs.4, 52, 62, 88 The Rach 1991 RCT reported that randomized allocation was performed only for the first 5 of 43 children entering the trial; each subsequent child was allocated to the treatment group that would lead to the smallest imbalance. While this allocation scheme is reminiscent of “minimization”-based randomized allocation schemes, the RCT was judged to have a high risk of confounding bias.56 All studies had at least some incomplete outcome data for some subjects. The proportion of subjects with missing data increased in studies with longer term followup. The TARGET study employed missing data imputation to limit attrition bias.4 Most studies reported an intention to treat analysis. However, in many studies, there was a high rate of crossover to surgical interventions (TT, adenoidectomy, or both).

Description of Nonrandomized Comparative Studies Of the 25 NRCSs,64-87 9 compared TT with watchful waiting or medical treatment and 2

compared TT with myringotomy. Outcomes evaluated included hearing levels, persistence of middle ear effusion and composite outcomes (cure, recurrence). These studies are summarized in Table 2. For futher details, see Appendices C-E.

Six studies evaluated comparisons of children with cleft palate who had early vs. delayed vs. medical treatment of chronic OME and reported outcomes related to language development, hearing levels, persistence of middle ear effusion. One study compared TT with medical treatment in children with primary ciliary dyskinesia and evaluated hearing levels, persistence of middle ear effusion and need for further surgery.

Eight studies compared TT with TT & adenoidectomy, adenoidectomy alone or adenoidectomy & myringotomy.

Table 2. Summary of nonrandomized comparative studies (NRCSs) Study, Year,

PMID, Country Enrollment

period Comparators (N) Special populations

Covariate adjusted Outcome(s)

Coyte 2001 11309633 Canada72

1992-1997 TT (10602) & adenoidectomy vs. TT (26714) Yes Rate of rehospitalization;

reinsertion of TT

De Beer 2004 15224825 Netherlands74

2001 TT (51) vs. OME without TT (132) vs. control (174) Yes Hearing levels at 18 years

Forquer 1982 6184891 U.S.67 NR

TT (177) vs. medical treatment & delayed TT (170) vs. medical treatment (153)

No Hearing level; Middle ear effusion

Grievink 1993 8246466 Netherlands70

9/1990-2/1991

TT (37) vs. OME (151) vs. control (82) Yes Language ability

Hu 2015 26429601 U.S.85 2014 TT (12) vs. TT & adenoidectomy or

adenotonsillectomy (8) No Hearing level

Hubbard 1985 4039792 U.S.66 1/1979 Early TT (24) vs. late TT (24) Cleft palate No Hearing level

Kadhim 2007 1981-2004 TT (36532) vs. TT & Yes Need for further surgery

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Study, Year, PMID, Country

Enrollment period Comparators (N) Special

populations Covariate adjusted Outcome(s)

17279052 Australia76

adenoidectomy (7534)

Kobayashi 2012 22386274 Japan79 1996-1999 Early TT (82) vs. late TT (bilateral:

6 mo, unilateral: 3 mo) (100) Cleft palate No Language development

Kuşcu 2015 26545930 Turkey86 2008-2013 early TT (67) vs. late TT (22) vs.

no TT (65) Cleft palate No Hearing level, otoscopic findings

Li 2015 26281253 China84 2002 - 2012 TT (248) vs. Myringotomy (276) Cleft palate No Cure, Recurrence

Li 2015 26281253 China84 2003 - 2012 TT (78) vs. Myringotomy (168) Adenoidal

hypertrophy No Cure, Recurrence

Marshak 1980 6778336 Israel68 NR TT (29) vs. myringotomy &

adenoidectomy (29) No Middle ear effusion

Motta 2006 17465378 Italy77

1/1/2001-12/31/2001

TT & adenoidectomy (34) vs. adenoidectomy (40) No Middle ear effusion

Niclasen 2016 27063746 Denmark87

2001-2002 4+ episodes of OM (569) vs. 4+ episodes of OM& TT (999) Yes Behavioral and Learning

Difficulties

Peters 1994 8195687 Netherlands69

9/1990-2/1991 . Yes Educational attainment,

Reading & Spelling

Reiter 2009 19929085 Germany78

NR TT & palate cleft repair (50) vs. palate cleft repair (66) Cleft palate No Hearing level

Robson 1992 1431515 UK65 1976-1988 TT (38) vs. control (32) Cleft palate No Hearing level; Middle ear

effusion Schilder 1997 9372253 UK71 1990 TT (56) vs. control (102) Yes Hearing levels; Language &

Educational achievement Stenstrom 2005 16330739 Canada75

1985-1989 TT (38) vs. sulfisoxazole (27) No Long term hearing thresholds

Tian 2015 26103659 China83

1/2001-6/2013

TT & Adenoidectomy (40 ears) vs. Myringotomy & Adenoidectomy (58 ears)

No Composite Outcome (symptoms, otoscopy, hearing level, tympanography)

Wolter 2012 22883987 Canada80

1991-2009 TT (26) vs. medical treatment (18) Primary ciliary dyskinesia No

Hearing level; Middle ear effusion; Need for further surgery

Xu 2003 12930655 China73

9/1997-5/2000

TT & palate cleft repair (31) vs. palate cleft repair (31) Cleft palate No Hearing level

Yagi 1977 321716 Sudan64 NR

TT & myringotomy & adenoidectomy (100) vs. adenoidectomy (100)

No Middle ear effusion

Yousaf 2012 23855103 Pakistan81

6/2008-12/2011 TT (44) vs. myringotomy (26) No Middle ear effusion

Youssef 2013 24265883 Egypt82

3/2007-1/2009

TT & myringotomy +/- adenoidectomy (86) vs. laser myringotomy +/- adenoidectomy (86)

No Middle ear effusion

TT: Tympanostomy tubes, NR: not reported, mo: months

Risk of Bias: Nonrandomized Comparative Studies Only five studies used matching or multivariable regression methods to adjust for potential

confounders (e.g. baseline severity of middle ear disease). See Appendix F for detailed risk of bias assessments. Generally, the studies that did not adjust for confounding are at high risk of bias.

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Outcomes: Nonrandomized Comparative Studies The outcomes of NRCSs that evaluated behavioral, language and educational outcomes are

summarized in Table 10. The Coyte 2001 report analyzed hospital discharge records and found that treatment with TT

and adenoidectomy compared with TT alone was associated with a reduction in the likelihood of reinsertion of TT (RR 0.5 [95% CI: 0.5-0.6]) and the likelihood of readmission for conditions related otitis media (RR 0.5 [95% CI: 0.5-0.6]), with greatest benefit in children three years of age or older.72

Schilder 1997 compared hearing levels and mean duration of otitis media with effusion (OME) at seven to eight years between children treated with TT at two to four years of age, with a (retrospectively) matched group of children who were not treated surgically. Pure tone average hearing levels measured at 0.5 to 4kHz were 11.4 and 8.1 dB (P=0.19) for treated and control ears, respectively. Similarly, mean OME percentages were not significantly different between groups (P ≤ 0.08).71

Hearing Outcomes: RCTs Hearing thresholds (in dB) were reported by arm in 10 RCTs at various time points, allowing

estimation of comparative effects between interventions. Pure tone average (typically averaged over 500, 100, 2000, and 4000 Hz) hearing thresholds were extracted. Hearing thresholds were variably reported as: averaged over both ears, best and worst ear, and right and left ear. When multiple averages were reported, we extracted for analysis the worst ear and the right ear. Six RCTs reported hearing thresholds at 1 to 3 months (classified as “early”).4, 36, 44, 45, 55 Five RCTs reported hearing thresholds at 12 to 24 months (classified as “late”).4, 36, 55, 58, 62 The remaining 6 RCTs did not report information in enough detail to include in quantitative analyses and are described separately. The Mandel 1989 RCT stratified children by preintervention hearing thresholds.44 Patients with no significant hearing loss (≤ 20 dB bilaterally or ≤ 40 dB unilaterally) were randomized to watchful waiting, myringtomy, or TT. The 23 patients with significant hearing loss were randomized to myringotomy or TT only. We have included these two groups as separate RCTs in the meta-analysis.

Figure 6 shows the topology of the network for early hearing thresholds at 1 to 3 months. TT were the most common comparator, being compared in head-to-head trials with four interventions (all except for myringotomy with adenoidectomy). TT, TT with adenoidectomy, myringotomy, and watchful waiting have each been compared with at least two other interventions. By contrast antibiotic prophylaxis is compared only with TT and in only one trial, and myringotomy with adenoidectomy is compared only with TT with adenoidectomy, again only in one trial.

20

Figure 6. Network graph for early (1-3 months) comparisons for hearing thresholds

The network plot consists of nodes representing the interventions being compared and edges representing the available direct comparisons. The number of studies that include each comparison is indicated next to each edge (connecting lines with thickness proportional to this number).

Table 3 shows the combined direct and indirect data from the network meta-analysis for early hearing thresholds for all possible comparisons between the treatments. Bearing in mind that a difference in hearing thresholds of 10 dB is likely clinically important, it appears that interventions that ventilate the middle ear (TT and TT and adenoidectomy) improved hearing thresholds by -9.1 dB and -10.3 dB respectively, compared to watchful waiting, with 95% credible intervals that exclude a null effect in the 1- to 3-month time frame.

Table 3. Differences in early hearing thresholds (in dB, 1-3 months) TT -1.2 (-9.8, 7.2) 6.8 (0.3, 12.2) -1.4 (-14.0, 11.1) 9.1 (-0.4, 18.5) 9.1 (3.2, 14.5)

1.2 (-7.2, 9.8) TT + Adenoidectomy

8.0 (-2.1, 17.2) -0.2 (-9.4, 9.0) 10.3 (-2.4, 23.1) 10.3 (1.6, 18.6)

-6.8 (-12.2, -0.3) -8.0 (-17.2, 2.1) Myringotomy -8.2 (-21.2, 5.9) 2.3 (-8.3, 14.0) 2.3 (-4.0, 9.2)

1.4 (-11.1, 14.0) 0.2 (-9.0, 9.4) 8.2 (-5.9, 21.2) Myringotomy + Adenoidectomy

10.5 (-5.1, 26.3) 10.5 (-2.4, 22.9)

-9.1 (-18.5, 0.4) -10.3 (-23.1, 2.4) -2.3 (-14.0, 8.3) -10.5 (-26.3, 5.1) Antibiotic prophylaxis

0.0 (-11.3, 10.7)

-9.1 (-14.5, -3.2) -10.3 (-18.6, -1.6) -2.3 (-9.2, 4.0) -10.5 (-22.9, 2.4) -0.0 (-10.7, 11.3) Watchful waiting

Differences in hearing thresholds (dB) and 95% Credible Intervals in early (at 1-3 months) hearing thresholds among the 6 treatments in Figure 6. Each cell contains the difference of the comparison of the intervention in the corresponding row versus the intervention in the corresponding column. Negative numbers imply better outcomes for the first.

Myringtotomy

Myringotomy & Adenoidectomy Antibiotic Prophylaxis

Tympanostomy Tubes

Tympanostomy Tubes & Adenoidectomy Watchful Waiting

1

1

1

3

3

1

2

21

Table 4 lists the probabilities derived from the network meta-analysis that an intervention is the first, second, etc., most effective with respect to early hearing thresholds. Table 5 aggregates these probabilities and lists the probability that an intervention is among either among the three most effect or the three least effective. TT placement has a 97 percent probability of being the most effective intervention, followed by TT and adenoidectomy (96%) and myringotomy and adenoidectomy (91%). Watchful waiting has high probability (99%) of being one of three least effective interventions, together with antibiotic prophylaxis and myringotomy alone.

Table 4. Probabilities (percent) that an intervention ranks as the i-th most effective with respect to early hearing thresholds

Intervention 1st 2nd 3rd 4th 5th 6th

TT 19 22 56 2 0 0

TT + Adenoidectomy 32 49 15 3 1 0

Myringotomy 1 2 5 59 24 9

Myringotomy + Adenoidectomy

47 24 20 4 2 2

Antibiotic prophylaxis 1 2 3 19 28 46

Watchful waiting 0 0 1 12 44 42

Table 5. Probabilities (percent) that an intervention is among the three most effective with respect to early hearing thresholds

Intervention Probability (%) of being among the 3 most effective interventions

Probability (%) of being among the 3 least effective interventions

TT 97 3

TT + Adenoidectomy 96 4

Myringotomy 8 92

Myringotomy + Adenoidectomy 91 9

Antibiotic prophylaxis 6 94

Watchful waiting 1 99

As illustrated in Figure 7, when compared with watchful waiting at 1 to 3 months followup,

mean hearing thresholds improved (decreased) by average of 9.1 dB following TT and by 10 dB following TT with adenoidectomy. Credible intervals for these effects exclude zero. The credible intervals for comparisons between watchful waiting and myringotomy alone, myringotomy with adenoidectomy, and oral antibiotic prophylaxis were wide, but did not exclude a null effect.

22

Figure 7. Early (1 to 3 months) decrease (improvement) in mean hearing thresholds compared with watchful waiting

CrI= Credibility Interval; TT=Tympanostomy Tubes

Figure 8 shows the topology of the network for late (12 to 24 month) hearing thresholds.

Figure 8. Network diagram of late (12-24 months) comparisons for hearing thresholds

The network plot consists of nodes representing the interventions being compared and edges representing the available direct comparisons. The number of studies that include each comparison is indicated next to each edge (connecting lines with thickness proportional to this number).

Myringotomy & Adenoidectomy

Antibiotic Prophylaxis

Tympanostomy

Tympanostomy Tubes & Adenoidectomy

Watchful Waiting

1

1

2

1

23

Table 6 shows combined direct and indirect data from the network meta-analysis for late hearing thresholds for all possible comparisons between the treatments. Bearing in mind that a difference in hearing thresholds of 10 dB is likely clinically important, none of the point estimates for improvement in hearing loss are of this magnitude, and credible intervals are wide and include the null effect. However, there is a trend suggesting that interventions including adenoidectomy (TT with adenoidectomy) may be more effective than watchful waiting.

Table 6. Differences in late hearing thresholds (in dB, 1-3 months) Myringtomy & Adenoidectomy 4.6 (-3.9, 12.0) 4.3 (-2.4, 9.9) 0.5 (-4.1, 4.3) 4.3(-2.1, 10.2)

-4.6 (-12.0, 3.9) Prophylaxis -0.3 (-5.4, 4.7) -4.2 (-10.7, 2.8) -0.32 (-6.2, 6.2)

-4.3 (-9.9, 2.4) 0.3 (-4.7, 5.4) TT -3.8 (-8.2, 0.8) 0.01 (-3.3, 3.9)

-0.5 (-4.3, 4.1) 4.1 (-2.8, 10.7) 3.8 (-0.8, 8.2) TT & Adenoidectomy 3.8 (-0.6, 8.5)

-4.3 (-10.2, 2.1) 0.32 (-6.2, 6.2) 0.0 (-3.9, 3.3) -3.8 (-8.5 0.6) Watchful waiting

Differences in hearing thresholds (dB) and 95% Credible Intervals in early (at 1-3 months) hearing thresholds among the 5 treatments in Figure 8. Each cell contains the difference of the comparison of the intervention in the corresponding row versus the intervention in the corresponding column. Negative numbers imply better outcomes for the first.

Table 7 lists the probabilities derived from the network meta-analysis that an intervention is the first and second most effective with respect to early hearing thresholds. Table 8 aggregates these probabilities and lists the probability that an intervention is among either the three most effect or the three least effective. At 12 to 24 months, interventions that include adenoidectomy (TT & Adenoidectomy and Myringotomy & Adenoidectomy) have the highest probability of being most effective, whereas watchful waiting, TT alone, and antibiotic prophylaxis all have probability of 90 percent or greater of being least effective.

Table 7. Probabilities percent) that an intervention ranks as the i-th most effective with respect to late hearing thresholds

Intervention 1st 2nd 3rd 4th 5th

TT 1 4 27 48 21

TT + Adenoidectomy 33 59 5 2 1

Myringotomy + Adenoidectomy 59 29 6 3 3

Antibiotic prophylaxis 6 5 26 18 46

Watchful waiting 1 3 37 29 30

TT= Tympanostomy tube

24

Table 8. Probabilities (percent) that an intervention is among the two most effective with respect to late hearing thresholds

Intervention Probability (%) of being among the 3 most effective interventions

Probability (%) of being among the 3 least effective interventions

TT 5 95

TT & Adenoidectomy 92 8

Myringotomy & Adenoidectomy 88 12

Antibiotic prophylaxis 10 90

Watchful waiting 4 96

TT= Tympanostomy tube

As shown in Figure 9, by 12 to 24 months, the mean difference in hearing thresholds for TT alone, compared to watchful waiting is now centered on zero. The point estimates suggest that interventions that include adenoidectomy (TT with adenoidectomy and myringotomy with adenoidectomy) are more likely to be effective at 12 to 24 months, although 95% credible intervals do not exclude a zero mean difference.

Figure 9. Late (12-24 months) decrease (improvement) in mean hearing thresholds compared

with watchful waiting

TT= Tympanostomy tube; CrI= Credibility Interval

The results for the studies that reported measuring hearing thresholds, but did not report mean hearing thresholds needed for inclusion in the network meta-analysis are summarized below. In the MRC Multicentre Otitis Media Study Group 2004 report outcomes of a speech-in-noise automated toy test (SiN ATT), the authors hypothesized that a measure of understanding of speech in noisy situations may tap the disability experienced by children with OME. This study allocated children to receive TT, with or without adenoidectomy, or to medical management only and included 47 of 68 children also enrolled in the TARGET trial. They reported a significant treatment by baseline SiN ATT interaction (P=0.17), and concluded that children with poor

25

baseline SiN ATT are those most likely to benefit from surgery.48 Chaudhuri 2006 reported a comparison of hearing thresholds between groups of children randomized to various medical treatments, placebo, or TT with or without adenoidectomy.38 D'Eredità 2006 reported that hearing thresholds were normal at one year in both arms of a study comparing laser myringotomy to myringtomy with TT tubes in children, aged 2 to 6 years.39 Gates 1985 reported in a trial of children 4 to 8 years of age (54 week followup) that those randomized to myringotomy alone experienced 16 weeks of abnormal hearing (pure-tone average of 20 dB or greater) compared to 11 weeks in those who received TT (P = 0.001). Gates 1987 reported that children treated with adenoidectomy, TT, and adenoidectomy had normal hearing (< 20 dB) in the better ear 90 to 93 percent of the time, as compared with 81 percent of the time (P < 0.001) in group treated with myringotomy alone.89 Paradise 2001 reported measuring hearing thresholds, but did not report the results for the comparison of hearing thresholds.52 Velopic 2011 found no postoperative (after more than six months) differences in average pure tone audiometry or resolution of middle ear effusion between children treated with TT & adenoidectomy and those treated with adenoidectomy alone. Average air bone gap at 2000 Hz was lower in the TT & adenoidectomy group (P=0.03).61

Duration of Effusion Six RCTs 37, 44, 45, 52, 88 reported the mean proportion of time with middle ear effusion. By

multiplying this proportion by followup time in weeks, we estimate comparative effectiveness of interventions expressed as a mean difference in duration of effusion. Figure 10 shows the topology of the network for comparisons of the duration of middle ear effusion. Three trials directly compare TT and watchful waiting. The other comparators, which contribute indirect evidence, are myringotomy, myringtomy with adenoidectomy, TT and adenoidectomy.

26

Figure 10. Network graph for duration of middle ear effusion

The network plot consists of nodes representing the interventions being compared and edges representing the available direct comparisons. The number of studies that include each comparison is indicated next to each edge (connecting lines with thickness proportional to this number).

Myringotomy

Myringotomy &

Tympanostomy

Tympanostomy Tubes & Adenoidectomy

Watchful Waiting

2

2

1 2

2

4

3

1

27

The network plot consists of nodes representing the interventions being compared and edges representing the available direct comparisons. The number of studies that include each comparison is indicated next to each edge (connecting lines with thickness proportional to this number).

Figure 11 shows a trend toward greater effectiveness for TT with adenoidectomy than TT

alone. However, credible intervals are wide and cannot exclude a null effect for all interventions.

Figure 11. Decrease (improvement) in mean duration of middle ear effusion compared with watchful waiting

TT= Tympanostomy tube, CrI= Credibility Interval

As summarized in Table 9, TT and adenoidectomy and TT alone have moderately high

probability (79% and 62%, respectively) of being the most effective interventions to decrease mean duration of middle ear effusion. Conversely, watchful waiting has a 94 percent probability of being among the three least effective interventions.

Table 9. Probabilities (percent) that an intervention is among the two most effective with respect to duration of MEE

Intervention Probability (%) of being among the 2 most effective interventions

Probability (%) of being among the 3 least effective interventions

TT 62 38

TT + Adenoidectomy 79 21

Myringotomy + Adenoidectomy 12 88

Antibiotic prophylaxis 41 59

Watchful waiting 6 94

TT= Tympanostomy tube; MEE= Middle Ear Effusion

28

Quality of Life and Patient-Centered Outcomes Nine studies (5 RCTs, 4 NRCSs, and one that combined both designs) in 13 papers reported on 134 quality of life and patient-centered outcomes in 1665 children over multiple time points and arms. These studies reported only 14 outcomes with significant results (see Table 10).40, 46, 50-54,

56, 58, 62, 69-71, 87 The results varied in magnitude and direction, even across subscales of the same test.

Five studies reported on 43 different IQ and other cognitive outcomes. Of these, five had significant results. Paradise found that children who were not eligible for randomization into a RCT for tubes because their otitis media was below the threshold had a significantly better result in the spelling subtest of the of the Woodcock-Johnson III Tests of Achievement, but not on any other subtest at ages 9 to 11. However, they found that the group included in the trial and randomized to early intervention with tubes had a better outcome on overall functioning in the Impairment Rating Scales, also at 9 to 11 years of age.54 Peters 1994 found that after almost eight years, kids who had received TT in a nonrandomized study did significantly better on teacher’s evaluation of their narrative writing skills, though not their reading or math scores.69 Similarly, Hall 2009 found that at age 4.5 children who had been randomized to early surgery had better writing (adjusted OR 3.74, 95%CI 1.51 to 9.27) and language (adjusted OR 3.45, 95% CI 1.42 to 8.39) scores at school entry, though not better math or reading scores.40

Seven of the eight studies reported on 51 verbal outcomes, of which six were found to have significant differences. Paradise found a significant difference in nonword repetition at 4 years of age between children randomized to early versus delayed tympanostomy, and at 6 years of age among children randomized to early versus delayed tympanostomy, those who refused randomization, and those who were not deemed eligible due to lack of severity of OME. At both time points, the delayed treatment group performed slightly better (mean difference at 3 years -3.4, 95% CI -6.2 to -0.7; mean difference at 4 years -2, 95% CI -4.1 to -0.1). In grade 4, they found that those not eligible performed significantly better than both study arms on an oral reading fluency test, though those results were not replicated at any other time point. The not eligible group had significantly worse outcomes compared to the early treatment and randomization consult withheld groups on the Children's Version of the Hearing in Noise Test at 9 to 11 years old.50-54 In a small study of 27 children, Schilder 1997 found a significant difference in two language measure outcomes, but not on the three others. In word forms production, the tubes group performed significantly better (mean difference 26.4, SD 0.92), as well as in the auditory discrimination measure (mean difference 0.08, SD 0.03).71

Four of the nine studies reported on 35 behavioral outcomes, of which three had significant findings. Paradise found that the early surgery group performed better on the Child Behavior Checklist total problems subscale (largest mean difference 2; 95% CI 0.1 to 4.8) than the other groups at ages 9 to 11. At the same age, the early intervention group performed better on the Disruptive Behavior Disorders Rating Scale, impulsivity and overactivity factor subscale (largest mean difference 2; 95% CI 0.1 to 4.8)54 Niclasen reported a NRCS of performance on the Strengths and Difficulties Questionnaire (multiple subscales), parent and teacher version. They concluded that their findings suggest and association between 4 or more episodes of early otitis media treated with TT and behavioral and learning difficulties later in childhood.87 However, they do not report statistical tests of the contrasts between treated and untreated children.

Only two studies reported on quality of life outcomes: Paradise reported on measures of parental stress at various ages,50-54 and Vlastos 2011 reported on pediatric health related quality

29

of life.62 Neither found any significant differences. Full details for all outcomes are in Appendix G.

Table 10. Cognitive, verbal, behavioral, and quality of life outcomes Study, year Design (N)

Outcomes: number reported (number statistically significant*) Cognitive Verbal Behavioral Quality of Life

Rach 1991 RCT (43)56

2 (0)

Niclasen 2016 NRCS (1568)87

3(nr) 12 (nr)

Rovers 2000 RCT (187)58

2 (0)

Hall 2009 RCT (136)40

10 (2) 6 (0) 6 (1)

Maw 1999 RCT (127)46

4 (0) 2 (0)

Vlastos 2011 RCT (45)62

1 (0)

Paradise, 2001, 2003, 2004, 2005, 2007

RCT/NRCS (402/729)50-54

15 (2) 18 (4) 14 (2) 4 (0)

Peters 1994 NRCS (188)69

15 (1) 5 (0)

Grievink 1993 NRCS (183)70

1 (0) 9 (0)

Schidler 1997 NRCS (27)71

5 (2)

* No statistically significant effect of intervention on outcome (in either direction) reported †No statistical comparison reported.

RCT= Randomized Control Trial; NRCS= Nonrandomized Comparative Study, NR= Not Reported

30

Key Question 2 For children with recurrent acute otitis media, what is the effectiveness of tympanostomy tubes (TT), compared to watchful waiting with episodic or prophylactic antibiotic therapy, on the frequency and severity of otitis media, quality of life, and other patient-centered outcomes?

Description of Comparative Studies We identified 8 publications, reporting on 7 RCTs90-96 and 2 NRCSs.8, 93 A total 1049

patients were randomized. The Mattila 2003 paper described two groups, an RCT which randomly allocated treatment in 137 patients, and a NRCS in which parental choice determined treatment in169 patients.93 Grindler 2014, reported a cross-sectional comparison of quality of life outcomes in 1208 patients.8

Comparators Three RCTs90-92 compared TT placement with daily oral antibiotic prophylaxis. Two of these

studies included a comparison with placebo,90, 91 and Kujala 2012 compared TT placement with no treatment.95 The effectiveness of TT alone vs TT with adenoidectomy was evaluable in three studies.93-95

Population Characteristics Inclusion criteria were similar across studies, all required patients to have had three or more

episodes of AOM in the preceding 6 months, or (in three studies) 4 or more episodes in past 12 to 18 months.

Studies varied on whether they required the presence or absence of middle ear effusion. Gonzalez 1986, El Sayed 1996, Mattila 2003 and Hammaren-Malmi 2005 did not exclude patients with otitis media with effusion.90, 92-94 Conversely, Kujala 2012 and Casselbrant 1992 required patients to be free of middle ear effusion at time of assessment for surgery. 91, 95 For study details, see Appendixes C-E.

Risk of Bias The methodological and reporting quality of the included studies are generally of concern. In

the RCTs of patients with recurrent AOM, randomization and allocation concealment were appropriately implemented in only one study.95 Comparison groups were dissimilar or the comparability was unclear in most studies.90, 92, 93 Blinding was partially implemented in only one study.91 Randomization, group similarity and blinding could not be assessed in Hammarén-Malmi 2005.94

The cross-sectional NRCS was rated as high for risk of confounding bias (lack of adjustment for potential confounders and potential for selection bias).8

31

Outcomes

Randomized Comparative Studies

Frequency and Severity of Recurrent Acute Otitis Media We did not quantitatively pool the results, primarily because of the small number of studies and substantial heterogeneity in reported outcomes. The majority of studies were done prior to widespread use of the conjugate pneumococcal vaccine, in an era where antibiotic resistance was less common and prophylactic oral antibiotic therapy was more commonly used in clinical practice. Results are summarized by comparator below.

TT Versus Placebo or No Treatment Gonzalez 1986 reported on two related outcomes: the number of children with no further

episodes of acute otitis media and the number of ear infections per child during the 6 month followup period (attack rate). In the placebo group, three of 20 children had no further episodes of AOM, compared to 12 of 22 in the TT group (p=0.01). The placebo group had an attack rate of 2.0 compared to the TT group, which had an attack rate of 0.86 (p=0.006).

Casselbrant 1992 also reported the number of new episodes per group divided by the total number of child years of followup. In the placebo group, this rate was 1.08 versus 1.02 in the TT group (p=0.25). In the placebo group, 40 percent had no further episodes of AOM, compared to 35 percent in the TT group. However, TT placement significantly decreased the percentage of time with AOM compared to placebo (P<0.001).

Kujala 2012 reported failure rate (defined as at least two episodes of AOM in 2 months, three in 6 months or persistent effusion lasting at least 2 months), percent of children with no recurrent AOM, cumulative number of AOM episodes, and one year incidence rates. There was an absolute difference in the proportion of failures of -13 percent (95% CI -25 to – 01, P = 0.04), between the TT and control groups. Thus 7.7 children would need to be treated with TT to prevent one additional failure. The one-year incidence rate (infections per child per year) was 0.55 (95% CI -0.93 to -0.17) lower in the TT group compared to the control group.95

TT Versus Antibiotic Prophylaxis In the Gonzalez 1986 RCT, 54.5 percent of children in the TT group and 24 percent in the

sulfisoxazole prophylaxis group had no recurrent AOM (P = 0.02). The attack rate was 0.86 infections per child in the TT group and 1.4 in prophylaxis group (P = 0.08).90

Casselbrant 1992 reported a rate of 0.6 episodes of recurrent AOM per child-year children treated with Amoxicillin and a rate of 1.02 in their TT group (P = 0.001).91

El-Sayed found no difference in the treatment outcomes of children treated with trimethoprim/sulfamethoxazole compared to children treated with TT (P = 0.37).92

TT Versus TT and Adenoidectomy An RCT by Mattila 2003 found no difference in cumulative hazard of recurrent AOM or in

efficacy, defined as one minus the adjusted relative risk in randomized and nonrandomized comparisons of children who underwent TT with adenoidectomy compared with TT alone.93

In the Kujala 2012 study, there was no significant difference in the TT with adenoidectomy group compared to the TT only group in the number of failures (absolute difference −5%, 95%

32

CI −16 to 6, P = 0.37), in the time to failure (P = 0.29) or to the first AOM (P = 0.6), or in the proportion of children with no AOM episodes (absolute difference 1%, CI −13 to 15, P =1.0).95

A subsequent 2005 RCT, which enrolled 217 children, 162 of whom had recurrent AOM, again found no differences in the mean number of otitis media episodes overall or in the subgroup of children with recurrent AOM at enrollment.94

Quality of Life Outcomes Although Kujala 2012 found that insertion of TT tubes, without or without adenoidectomy,

significantly reduced the risk of recurrent AOM, a subsequent publication from the same trial examining quality of life outcomes at study entry, 4 months, and 12 months (assessed using the Otitis Media-6 questionnaire) found no differences in overall ear-related quality of life between surgically treated groups and no surgery groups, nor did they find any differences in the subscales of caregiver concern, emotional distress, physical suffering, activity limitations, hearing loss, or speech impairment.96

Nonrandomized Comparative Studies A cross sectional study by Grindler et al. reported both disease specific quality of life

outcomes utilizing OM-6 score, and health related quality of life using the PedsWL Infant Impact Module in 1208 patients. The OM-6 score was higher (reflecting worse otitis specific quality of life) in children in otolaryngology practices who had been recommended to undergo TT placement than in children with prior TT placement.8

Key Question 2a What factors (such as age, age of onset, number of recurrences, presence of persistent middle ear effusion, comorbidities, sociodemographic risk factors, history of complications of acute otitis media, antibiotic allergy or intolerance) predict which children are likely to benefit from the intervention? There are no prospective planned comparisons evaluating whether the presence of middle ear

effusion (at time of surgical evaluation) modifies the effectiveness of TT placement for recurrent AOM. Gonzalez 1986 report a retrospective subgroup comparison based on the presence or absence of middle ear effusion at initial evaluation and conclude that the attack rate, as well as the number of patients who had no further bouts of AOM, was significantly better (p < 0.05) in those children without middle ear effusion. However, this group consisted of only 22 patients.90 Two studies specifically excluded patients with middle ear effusion at time of surgical evaluation.91,95

Casselbrant 1992 analyzed data with a multivariable Poisson model and concluded that TT reduced the number of episodes of AOM/otorrhea only in those subjects whose episodes of AOM occurred year-round. In their model, younger age and white race were significantly associated with higher rates of recurrent AOM, but treatment by age and treatment by race interactions were not found.91

33

Key Question 3 What adverse events, surgical complications, and sequelae are associated with inserting tympanostomy tubes (TT) in children with either chronic otitis media with effusion or recurrent acute otitis media?

We extracted descriptive data on the occurrence of 11 adverse events from 85 prospective surgical studies enrolling at least 50 subjects (including arms of RCTs or NRCSs with 50 or more patients) and population-based retrospective single-group studies (registry studies) with at least 1000 subjects. Adverse events were also extracted from a treatment arm (if it included at least 50 patients) 10 RCTs and NRCSs identified for KQs 1 and 2. The adverse events extracted included perioperative complications, otorrhea, tube blockage, granulation tissue formation, premature extrusion, displacement of the TT into the middle ear space, persistent perforation, myringosclerosis, presence of atrophy, atelectasis or retraction, cholesteatoma, and long-term hearing loss. We did not consider other adverse events, such as antibiotic resistance, gastrointestinal side effects of antibiotics, or pain related to ear drops.

Table 11 provides a highly summarized summary of number of publications (some publications reported several cohorts summarized separately) that reported numbers of patients (or ears) for each adverse event. We do not estimate the frequency of adverse events in a population, rather a descriptive summary of observed median and range of estimates in studies.

Table 11. Adverse events associated with TT placement Adverse Event N

publications Patients: Median Percent [25%, 75th%]

Ears: Median Percent (25%, 75th%)

Perioperative Complications 495, 97-99 NA NA Otorrhea 3917, 36, 42, 88, 97,

100-133 20.6 [13.1, 47.3] 10.4 [9.1, 28.2]

Tube Blockage 1897, 99, 103, 123,

127, 130-142 9.0 [ 2.6, 10.7] 4.0 [2.8, 17.1]

Granulation Tissue 1236, 106, 109, 110,

118, 127, 130-132, 134,

136, 143 3.3 [ 2.9, 5.7] 3.9 [1.8, 5.7]

Premature Extrusion 18112, 115, 118, 123,

125, 127, 129, 130, 136,

140, 144-151 13.3 [ 7.1,47.9] 4.1 [1.6, 14.0]

TT Displacement into middle ear 8127, 130, 134, 135,

143, 145, 152, 153 NA 0.8 [0.7, 0.9]

Persistent Perforation 4836, 44, 52, 61, 74,

91, 100, 101, 103, 105,

107, 108, 110, 116-118,

121, 122, 127, 129-131,

133-136, 138, 143-145,

147, 148, 150, 152-166

2.7 [1.8, 6.7] 2.9 [ 2.0, 5.3 ]

Myringosclerosis 2236, 52, 61, 74, 122,

130-132, 134, 135, 148,

150, 152, 155, 157, 163,

167-172

33.5 [5.0, 38.0] 17.1 [6.8, 43.9]

Atrophy, Atelectasis or Retraction 2252, 61, 100, 121,

122, 130, 131, 133, 136,

148, 149, 153, 155, 157,

161, 163, 166, 168, 170,

173-175

13.9 [7.5, 25.9] 14.4 [ 5.0, 32.8]

Cholesteatoma 2488, 100,

108, 115, 122, 127, 131-

134, 136, 143, 145-147, 0.9 [0.2, 1.8] 0.7 [ 0.1 ,3.2 ]

34

Adverse Event N publications

Patients: Median Percent [25%, 75th%]

Ears: Median Percent (25%, 75th%)

155, 162, 167, 168, 173,

176-179 Hearing Loss 1099, 112, 114, 123,

129, 135, 148, 156, 167,

170 8.0 [ 1.2, 19.2] NA

NA: Not calculated when number of patients (ears) < 5.

TT=Tympanostomy Tubes

See Appendix H for an evidence map and study specific details. In general, the study

specific definitions of adverse events were poorly reported and/or highly variable between studies. Not all cohorts followed all patients until extrusion of the tube, nor was followup complete in all studies.

Perioperative adverse events were described in 4 studies.95, 97-99 Of these, three studies95, 97,

99 reported surgical adverse events including ear canal abrasion, tympanic membrane tear and hemorrhage. The 2002 report by Hoffman98, reported perioperative events in 0.81% of 3198 patients. Isaacson, 2008 report no operative deaths in a prospective series of 10,000 tube insertions.99

Otorrhea was reported in 39 publications. Otorrhea is particularly complex to characterize, as it may differ with respect to frequency, duration, volume, character (e.g. purulent vs. clear) and associated signs and symptoms (such as pain, fever or odor). Studies had different durations of followup, and used multiple categorical definitions (e.g. at least one episode or more than 3 episodes).

Tube blockage was reported in 18 publications. The median percentage of patients with TT blockage was 6.7% across studies. Duration of followup ranged from 2 weeks postoperative to time of extrusion or removal. In most cases, it was not possible to determine if occlusion was temporary or permanent.

Granulation Tissue was reported as an adverse event in 12 publications. In most cases studies did not report the clinical impact or symptoms associated with this finding.

Premature Extrusion was reported in 18 studies. Studies often either did not define what time interval was considered premature. The interquartile range for percent of premature extrusion was wide, likely due in large part to highly variable definitions.

TT displacement into the middle ear, reported in 9 studies. Persistent Perforation of the tympanic membrane after TT extrusion or removal was

reported in 49 publications in a median of 2.7 percent of patients. The majority of studies did not report the duration, associated symptoms or whether these were surgically repaired.

Myringosclerosis, reported in 22 studies, and Atrophy, Atelectasis or Retraction (also reported in 22 studies) were common, but definitions were variable and often poorly described.

Cholesteatoma was reported in 25 studies and Hearing Loss in 10 studies.

Key Question 4 Do water precautions reduce the incidence of tympanostomy tube otorrhea or affect quality of life?

35

Description of Comparative Studies We identified 11 publications which reported 2 RCTs180, 181 and 9 NRCSs182-190

RCTs The RCTs are briefly summarized in Table 12. In the Goldstein 2005 study180 children in the

“ear plugs group” were instructed to wear ear plugs when bathing, showering and washing hair. The “no precautions” group was allowed to swim or bathe without ear plugs. Parents were given a calendar to record all swimming and bathing activities. A subgroup of children with 125 or more instances of water exposure was reported. The Parker 1994181 RCT assigned children to a nonswimming group and a swimming group (without earplugs or other precautions).

36

Table 12. RCTs: Water precautions — one or more episodes of otorrhea Study PMID Enrollment dates Country (Design)

Followup time Intervention Population n/N (%) Odds ratio (95% CI)

Goldstein 2005 15689760

7/1996-6/1999 U.S.180

1 year Ear plugs All Participants

42/90 (46.7) 0.68 (0.37 – 1.25)

No precautions All Participants

46/82 (56.1) [reference]

Ear plugs Children who each had ≥ 125 instances of water exposure

29/39 (74.3) 2.69 (0.95 – 7.64)

No precautions Children who each had ≥ 125 instances of water exposure

14/27 (51.8) [reference]

Parker 1994 8024107 12/1989-2/1991 U.S.181

1 year Nonswimming All Participants

18/30 (60.0) 0.71 (0.29 – 1.76)

Ear plugs† All Participants

13/15 (86.7) 3.10 (0.64 – 15.04)

No precautions All Participants

42/62 (67.7) [reference]

†Randomized to the nonswimming group, but self-selected to swim using ear precautions (e.g., ear plugs, wax, cotton with petroleum jelly) – considered an nonrandomized comparative studyin the meta-analysis.

RCT=Randomized Control Trial; CI= Confidence Interval

NRCS In two of the 9 NRCSs, otorrhea was reported only as episodes-per-ear (not per patient) in

children who chose to swim versus those who chose not to swim. Both studies report similar proportions of ears with otorrhea in swimmers and nonswimmers (6.4% vs. 6.9%188) and 23% vs. 18%190) and are not considered further.

The remaining 7 NRCSs (shown in Table 13) compared two alternate forms of water precaution (ear plugs or prohibition of swimming) versus no precautions (children allowed to swim without ear protection). Children permitted to swim were often instructed to avoid of high risk activities (e.g., diving, underwater swimming). See Table 13 and Appendixes C-E for study details.

Table 13. NRCSs: Water precautions—one or moreepisodes of otorrhea Becker 1987 3586818 4/1985-9/1985 U.S. (NRCS)182

≥ 2 months Nonswimming All Participants 9/30 (30) 2.31 (0.67 – 7.94) Ear plugs All Participants 7/23 (30.4) 2.36 (0.64 – 8.70) No precautions All Participants 5/32(15.6) [reference]

Cohen 1994 8289048 1990-1992 Israel183

2.5 years Nonswimming All Participants 2/20 (10.0) 1.11 (0.14 – 8.72) No precautions All Participants 2/22 ( 9.1) [reference]

el Silimy 1986 3780019 [No dates] UK184

6 months Nonswimming All Participants 14/41 (34.1) 2.07 (0.78 – 5.50) No precautions All Participants 9/45 (20.0) [reference]

Francois1992 1485779 [No dates] France 185

3-4 months Nonswimming All Participants 21/68 (30.1) 2.89 (1.43 – 5.86)

No precautions All Participants 19/142 (13.3) [reference]

37

Kaufmann 1999 10546304 1/1996-1/1997

Switzerland186

≥ 3 months Ear plugs All Participants 4/16 (25.0) 0.59 (0.16 – 2.11) No precautions All Participants 17/47 (36.2) [reference]

Salata 1996 8607955 [No dates] U.S. 187

1.5 years Nonswimming All Participants 7/116 (6.0) 0.34 ( 0.14 – 0.82) Ear plugs All Participants 12/44 (27.3) 1.92 (0.88 – 4.42) Ear drops All Participants 23/101 (22.8) 1.55 (0.81 – 2.98) No precautions All Participants 22/138 (15.9) [reference]

Smelt 1984 653821 [No dates] UK189

≥ 2 months Nonswimming All Participants 6/40 (15.0) 2.35 (0.55 – 10.12) No precautions All Participants 3/43 ( 7.0) [reference]

95% Confidence intervals that exclude a null effect are shown in bold

Risk of Bias The Goldstein 2005 RCT was rated high risk of bias for allocation concealment and blinding

of participants (investigators were blinded), but otherwise risk of bias was low or unclear. The Parker 1994 RCT was rated as high risk of bias for random sequence generation (use of social security numbers), blinding of participants, incomplete outcome data (only 105 of 212 available for followup), lack of an intention-to-treat analysis. (15/45 assigned to nonswimming group self-selected to swim and are analyzed as an NRCS), and compliance bias. All of the NRCSs had high risk of selection biases since patient assignment was based on parent and/or patient choice.

Outcomes Goldstein 2005 reported a slightly lower adjusted rate of otorrhea randomly assigned to use

ear plugs (0.07 episodes/month in intervention group versus 0.10 episodes/month in the control group, P=0.05).

The summary odds ratio reported by Goldstein was 0.68 (95% CI 0.37 to 1.25). Parker 1994 reported a summary odds ratio of 0.71 (95% CI 0.29 to 1.76)

Figure 12 summarizes our random effects meta-analysis of NRCSs, with separate summary estimates for each of the two forms of water protection (ear plugs and avoidance of swimming). The summary odds ratio comparing ear plugs versus no precautions of having one or more episodes of otorrhea was 1.7 (95% CI 0.95 to 3.06). The odds ratio for nonswimming compared to no precautions was 1.52 (95% CI 0.71 to 3.25). It is notable that event rates in the RCTs are generally higher in both control and intervention arms, compared with lower event rates in the NRCSs, possibly reflecting better ascertainment of episodes of otorrhea in the RCTs.

Overall, aside from the small reduction in mean number of episodes of otorrhea found in Goldstein 2005, the available evidence suggests that ear plugs or avoidance of swimming does not reduce the risk of swimming-related otorrhea.

38

Figure 12. NRCSs only, children with one or more episodes of otorrhea

OR = Odds ratio (values greater than 1 favor ‘no precautions’ arms; values less than 1 favor the intervention (ear plugs or nonswimming); NRCS=Nonrandomized Comparative Study; CI= Confidence Interval

39

Key Question 5 In children with tympanostomy tube otorrhea, what is the comparative effectiveness of topical antibiotic drops versus systemic antibiotics or watchful waiting on duration of otorrhea, quality of life, or need for tube removal?

We identified 14 publications,19, 139, 142, 190-200 representing 11 studies (10 RCTs and 1

NRCS), with a total of 1811 patients analyzed (1405 in RCTs and 406 in the NRCS) that assessed the effectiveness of various interventions to treat TT otorrhea. The results and arm details of these studies are given in Table 14. For full study details, see Appendixes C-E.

Risk of Bias Risk of bias was low for random sequence generation and allocation concealment. However,

8 of 11 studies had high risk of bias due to open label design, which precluded blinding of personnel and care providers.

Table 14. Effectiveness of various interventions to treat TT otorrhea

Study Year, PMID, Enrollment Period, Country Intervention Details Responders N

Dohar 1999 10326811 U.S.194 ofloxacin eardrops 119 141 unclear - historical practice 140 218 unclear - current practice 33 47 Dohar 2006 16880248 5/2003-5/2004 U.S. & Finland142 NRCS ciprofloxacin/dexamethasone ear drops 33 39

oral amoxicillin–clavulanate 24 41 Goldblatt 1998 10190709 U.S. ofloxacin eardrops 107 140 oral amoxicillin–clavulanate 101 146 Granath 2008 18565598 -2/1998-12/2002 Sweden197 hydrocortisone + oxytetracycline + polymyxine 12 15

hydrocortisone + oxytetracycline + polymyxine & oral amoxacillin +/- clavulinate 19 22

Heslop 2010 20979100 5/2003-5/2007 Chile198 ciprofloxacin ear drops 17 22

oral amoxicillin 6 20 saline rinse 12 26 Roland 2003 14660913 3/2000-2/2001 U.S. 196 ciprofloxacin/dexamethasone ear drops 72 87

ciprofloxacin ear drops 72 80 Roland 2004 14702493 U.S.139, 191, 201 ciprofloxacin/dexamethasone ear drops 174 207 ofloxacin eardrops 153 216 Ruohola 1999 10190921 03/1996-05/1997 Denmark193 oral amoxicillin & oral prednisolone 22 23

oral amoxicillin 24 27 Ruohola 2003 12728089 09/1998-06/1999 Finland 195 oral amoxicillin–clavulanate 28 34

oral placebo 13 32 Strachan 2000 10865480 UK202 neomycin/polymyxin B/hydrocortisone (drops) 24 29 neomycin/dexamethasone 19 29 van Dongen 2014 24552319 6/2009-5/2012 Netherlands 19, 199

hydrocortisone–bacitracin– colistin eardrops 72 76

oral amoxicillin–clavulanate 43 77 initial observation 34 75

40

TT= Tympanostomy Tubes; NRCS= Nonrandomized Comparative Study

The studies reported multiple comparisons, summarized in Figure 13, including oral antibiotics (amoxicillin and amoxicillin/clavulinate), various antibiotic drops, and various antibiotic-glucocorticoid drops, oral corticosteroids, and combinations. Treatment arms grouped in the watchful waiting/placebo category included watchful waiting,199 oral placebo195 and topical saline wash.198

Figure 13. Network of treatment comparisons (RCTs)

Two studies are not shown in network graph: 1) Dohar 1999 (undefined comparators. 2) Roland 2004 (comparison of two topical antibiotic-glucocorticoid treatments). Studies with the treatment arms show as dotted lines do not contribute indirect information, and are excluded from the network meta-analysis. The network plot consists of nodes representing the interventions being compared and edges representing the available direct comparisons. The number of studies that include each comparison is indicated next to each edge (connecting lines with thickness proportional to this number).

PO= Oral; RCT= Randomized Control Trial

Outcomes

Clinical Cure Eleven studies reported the number of clinically cured patients in each arm, often at multiple

timepoints. All studies reported additional intermediate outcomes (e.g., cessation, improvement, or duration of otorrhea). For the meta-analysis, we chose the time designated by each of these studies as the test of cure (range 7 to 20 days after initiation of treatment).

Four studies were excluded from the network meta-analysis. In two studies, this related to the intervention. Dohar 1999194 NRCS reported clinical cure in 84.6 percent of 143 patients treated with topical ofloxacin in compared to a 64.2 percent in a historical practice group (n=218) and a

Topical Antibiotic-Glucocorticoid

Topical Antibiotic-Glucocorticoid & PO Antibiotic Topical Antibiotic

PO Antibiotic

Oral Antibiotic & PO Glucocorticoid Watchful Waiting or Placebo

1 2 1

1

2

1 3

2

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70 percent clinical cure rate in a concurrent practice group (n=47). However, the specific treatments used in the historical practice group and concurrent practice group were not reported. The second excluded study, Strachan 2000 202, compared an antibiotic-glucocorticoid topical drop containing neomycin sulfate, polymyxin B sulfate and hydrocortisone with a topical spray formulation containing neomycin sulfate and dexamethasone. They concluded that topical treatment with a nonpressurized ear spray was easier to use and caused less discomfort than ear drops. However, they found no overall difference in number of patients cured.. Two studies193, 197 compared dual interventions (i.e. topical antibiotic-glucocorticoid and oral antibiotic, oral antibiotic and oral glucocorticoid) and were not included in the network meta-analysis, as they contributed no indirect evidence for the comparisons of primary interest.

The pairwise comparative effects of interventions are shown in Table 15. Treatment strategies that include topical antibiotic-glucocorticoid drops predominate over oral antibiotics and watchful waiting or placebo. Treatment strategies that include topical antibiotic-glucocorticoid drops predominate over oral antibiotics and watchful waiting or placebo.

Table 15. Network meta-analysis of interventions for otorrhea Topical Antibiotic-Glucocorticoid -0.49 (-2.03, 1.08) -1.68 (-3.32, -0.16) -2.46 (-4.4, -0.6)

0.49 (-1.08, 2.03) Topical Antibiotic -1.19 (-2.82, 0.31) -1.97 (-3.94, -0.14) 1.68 (0.16, 3.32) 1.19 (-0.31, 2.82) Oral Antibiotic -0.78 (-2.33, 0.78) 2.46 (0.6, 4.4) 1.97 (0.14, 3.94) 0.78 (-0.78, 2.33) WW or Placebo

Ab-GC: Antibiotic-glucocorticoid. Differences in Log Odds Ratios with 95% Credible Intervals for clinical cure of otorrhea among the 4 treatments in Figure 13. Each cell contains the odds ratio for the comparison of the intervention in the corresponding row versus the intervention in the corresponding column.

WW= Watchful Waiting

Table 16 lists the probabilities derived from the network meta-analysis that a particular intervention is ranks first to fourth most effective. The probability rankings suggest: 1) treatment strategies that include topical antibiotic drops predominate treatment with oral antibiotics and 2) all active treatments are more effective than watchful waiting/placebo.

Table 16. Probabilities (%) that an intervention ranks as the i-th most effective with respect to clinical resolution of otorrhea

Intervention 1st 2nd 3rd 4th

Topical Antibiotic-Glucocorticoid 77 21 1 0

Topical Antibiotic 22 73 5 1

Oral antibiotic 1 5 83 12

Watchful waiting/placebo 0 1 12 87

Figure 14 illustrates the relative effectiveness of each intervention compared to watchful waiting or placebo. Treatment with either topical antibiotic-glucocorticoid or topical antibiotic are superior to watchful waiting/placebo.

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Figure 14. Relative effectiveness of various interventions compared to watchful waiting or placebo

CrI= Credibility Interval; OR= Odds Ratio

Figure 15 illustrates the relative effectiveness of each intervention compared to oral antibiotics. Treatment with topical antibiotic-glucocorticoid is superior to oral antibiotics. The relative effectiveness of topical antibiotic (without glucocorticoid) compared to oral antibiotics suggests greater effectiveness, but the credible interval includes one.

Figure 15. Relative effectiveness of interventions compared to oral antibiotics

CrI= Credibility Interval; OR= Odds Ratio

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Quality of Life A single study (summarized in Table 17) reports quality of life outcomes related to our

comparative effectiveness questions. Van Dongen 2014 evaluated quality of life in 230 children with otorrhea who received either watchful waiting, oral antibiotics, or antibiotic-glucocorticoid drops for 7 days.199 At baseline, the generic and disease-specific health-related quality-of-life scores indicated good quality of life and were similar across the groups. At 2 weeks of followup, the change in the generic health-related quality-of-life scores did not differ significantly among the study groups. The changes in the disease-specific health-related quality-of-life scores at 2 weeks were small but consistently favored ear drops. The minimal clinically important difference for the generic Quality of Life instrument used in Van Dongen 2014 (CHQ-PF28) is not clear. Using as reference the range of the score, which is between 1 and 35 with higher values implying better quality of life, the 95% confidence intervals for the within group differences are judged to be large; thus it is possible that the Van Dongen 2014 trial results cannot exclude clinically important differences.

Table 17. Quality of life outcomes

Author Outcome Timepoint Arm N analyzed Baseline median (range)

Within Arm Median Difference (range)

P value

van Dongen 2014 24552319 25896832 6/2009-5/2012 Netherlands

Quality of life (CHQ-PF28, lower scores indicate better QOL)

2 weeks watchful waiting

77 14 (5, 33) 0.5 (-15, 26) NS

19, 199, 200 oral antibiotic 77 15.5 (6, 28) 1 (-11, 18) NS antibiotic-

glucocorticoid drops

76 15.5 (6, 29) -1 (-14, 11) NS

QoL= Quality of Life, NS= not signficant

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Discussion Overall Summary and Strength of Evidence

Our systematic review of 172 publications focused on five Key Questions (KQ), which evaluate the evidence for the effectiveness of tympanostomy tubes (TT) in children with chronic middle ear effusion and recurrent acute otitis media, the adverse events (harms) associated with this procedure, the need for water precautions in children with TT, and the treatment of TT otorrhea.

Key Question 1 In children with chronic otitis media with effusion, 32 publications reported results of 22

RCTs. Hearing thresholds were obtained in 16 RCTs, and in 10 trials they were reported by arm at various time points.

TT placement (compared to watchful waiting) resulted in improved average hearing thresholds 1 to 3 months after surgery. During this period, when the majority of tubes are functioning, mean hearing thresholds decreased by an average of 9.1 dB (95% CrI -14 to -3.4). A similar improvement was seen for children treated with TT and adenoidectomy (10 dB [95% CrI -19 to -1.9]) improvement. No significant change in hearing thresholds was noted after treatment with myringotomy alone or with oral antibiotic prophylaxis.

By 1 to 2 years, when most tubes have extruded, hearing thresholds are no longer different, likely reflecting the favorable natural history of spontaneous resolution of middle ear effusion in most children. There was a trend suggesting improved thresholds in children undergoing adenoidectomy, but credible intervals are wide and include the null effect.

The IPD by Boonacker et. al., which relied on a post hoc composite outcome, concluded that adenoidectomy is most beneficial in children four years or older with persistent otitis media with effusion. In this group at 12 months, 51% of those who had adenoidectomy failed, whereas 70% of those who did not have adenoidectomy failed (Risk Difference 19%: 95% Cl 12% - 26%; NNT = 6). No significant benefit of adenoidectomy was found in children less than 4 years old.2

Data were very sparse with respect to which factors might predict those children more likely to benefit from TT. The individual patient data meta-analysis (IPD) reported by Rovers et. al. focused on interactions between treatment and baseline characteristics. They found significant interactions between daycare attendance in children 3 years or younger, and in children over 4 years of age with a hearing level of 25 dB or greater in both ears, and concluded that TT might be used in young children attending day-care; or in older children with a hearing level of 25 dB or baseline hearing level persisting for at least 12 weeks. They noted that average hearing level at baseline did not obviously modify the effect estimate.203

Quality of life and other patient-centered outcomes (cognitive, language, and behavioral) were reported in eight studies (five RCTs, three NRCSs, and one that combined both designs) in 12 papers. These studies reported on 119 quality of life and patient-centered outcomes in 1665 children over multiple time points and interventions. These studies reported only 14 outcomes with significant results. In general, the results were not significant and varied in magnitude and direction, even across subscales of the same test.

Overall, the evidence suggests that TT placement results in improved average hearing thresholds during early followup of 1 to 3 months after surgery. However, these improvements are not sustained at 1 to 2 years. There is limited evidence regarding quality of life outcomes, but

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neither of the two studies that evaluated parental stress and health related quality of life found significant improvements in surgically treated children. Evidence for improved cognitive, language, or behavioral outcomes after TT compared to watchful waiting is similarly lacking.

Key Question 2 In children with recurrent acute otitis media, seven publications reported results of six RCTs.

We were unable to provide pooled results due to the small number of studies, multiple interventions, and heterogeneity in reported outcomes. The limited available evidence suggests that TT placement decreases the number of further episodes and the overall number of episodes of recurrent AOM.

Although Kujala 2012 found that insertion of TT, without or without adenoidectomy, significantly reduced the risk of recurrent AOM, a subsequent publication of quality of life outcomes from this trial found no differences in overall ear-related quality of life between surgically treated groups and no-surgery groups, nor did they find any differences in the subscales of caregiver concern, emotional distress, physical suffering, activity limitations, hearing loss, or speech impairment.96

Very little evidence from RCTs is available to evaluate factors that identify children most likely to benefit from TT placement. A post hoc subgroup (n=22) comparison in one study concluded that patients with middle ear effusion at the time of surgical evaluation had improved outcomes.90 The other two studies specifically excluded patients with middle ear effusion.91, 95

Three RCTs consistently found no difference in recurrent episodes of AOM when comparing TT versus TT and adenoidectomy. However, the Boonaker 2014 IPD meta-analysis concluded that children less than 2 years old years with recurrent AOM had a greater chance of clinical improvement. In this younger group at 12 months, 16% of those who had adenoidectomy failed, whereas 27% of those who did not have adenoidectomy failed [RD 12%, 95% Cl: 6% to 18%; NNT = 9].2

Key Question 3 In general, study specific definitions of adverse events were incompletely reported or highly

variable between studies. Not all cohorts followed all patients until extrusion of the tube, nor was followup complete in all studies. Several adverse event categories have very wide interquartile ranges (e.g. otorrhea, premature extrusion, and myringosclerosis). This is likely because of highly variable definitions. For example, in some studies, counts of patients with at least one episode of otorrhea were included, while other studies included only patients with purulent ear discharge. Otorrhea is particularly complex to characterize, as it may with respect to frequency, duration, volume, character, and associated symptoms. Other adverse events, such as hearing loss and cholesteatoma, are likely confounded by the severity of preexisting and ongoing middle ear disease.

Key Question 4 We identified nine studies, two RCTs and seven NRCSs that evaluate physical ear protection

(e.g. ear plugs) or water restriction (e.g. no swimming or head immersion while bathing) in children after TT placement. A single RCT reported a slightly lower adjusted rate of otorrhea in children assigned to wear ear plugs. The unadjusted odds ratio of having one or more episodes of otorrhea was not significantly different (OR 0.68, 95% CI 0.37 to 1.25). A second RCT, with

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high risk of bias, found a nonsignificant difference in the odds ratio in nonswimmers versus swimmers (OR 0.71, 95% CI 0.29 to 1.76). Separate meta-analysis of NRCSs with evaluated ear protection and nonswimming tend to favor no precautions and swimming, but their confidence intervals do not exclude a null effect. In addition, the included NRCSs have high risk of confounding and other biases.

Key Question 5 Seven studies were included in a network meta-analysis of the comparative effectiveness of various treatments for TT otorrhea. The common outcome evaluated was clinical cure, defined as absence of otorrhea after completion of treatment.

The odds of clinical cure were 12-fold (95% CrI: 1.9 – 82) higher [NNT 2.2 (assuming a baseline rate 0.45)]a for antibiotic-glucocorticoid drops, compared to watchful waiting/placebo. Similarly, the odds of clinical cure were 7.3-fold (95% CrI: 1.2 – 51) higher [NNT 2.5 (assuming a baseline rate of 0.45)]b for topical antibiotic drops (compared to watchful waiting/placebo).

Compared to oral antibiotics, treatment with topical-glucocorticoid drops demonstrated higher effectiveness, odds ratio 5.3 (95% CrI: 1.2 to 27) [NNT 3.2 (assuming a baseline rate 0.56)].c The odds ratio for topical antibiotic drops was 3.3 (95% CrI: 0.74 – 16)[NNT 5 (assuming a baseline rate of 0.69)]d, although the credible interval includes 1.

a As seen in: van Dongen TM, van der Heijden GJ, Venekamp RP, et al. A trial of treatment for acute otorrhea in children with tympanostomy tubes. N Engl J Med. 2014 Feb 20;370(8):723-33. doi: 10.1056/NEJMoa1301630. PMID: 24552319. (34 of 75 in watchful waiting arm) b As seen in: Heslop A, Lildholdt T, Gammelgaard N, et al. Topical ciprofloxacin is superior to topical saline and systemic antibiotics in the treatment of tympanostomy tube otorrhea in children: the results of a randomized clinical trial. Laryngoscope. 2010 Dec;120(12):2516-20. doi: 10.1002/lary.21015. PMID: 20979100. (12/26 cured in saline rinse (placebo) arm) c As seen in: van Dongen TM, van der Heijden GJ, Venekamp RP, et al. A trial of treatment for acute otorrhea in children with tympanostomy tubes. N Engl J Med. 2014 Feb 20;370(8):723-33. doi: 10.1056/NEJMoa1301630. PMID: 24552319. (43 of 77 cured in oral antibiotic arm) d As seen in: Goldblatt EL, Dohar J, Nozza RJ, et al. Topical ofloxacin versus systemic amoxicillin/clavulanate in purulent otorrhea in children with tympanostomy tubes. Int J Pediatr Otorhinolaryngol. 1998 Nov 15;46(1-2):91-101. PMID: 10190709. (101 of 146 cured in oral antibiotic arm)

An overall summary of main conclusions with an assessment of the strength of evidence is

summarized in Table 18.

Table 18. Strength of evidence assessment Key Question or Population

Outcome Comparison Risk of Bias for the evidence-base

Consistency Precision Directness Overall Rating

Key Findings and Comments

Key Question 1 Effectiveness of TT in children with chronic MEE

Improvement (decrease) in mean hearing level 1-3 months

TT vs. Watchful waiting

Moderate to high

Consistent Somewhat imprecise

Mix of direct and indirect from network MA

Moderate 6 RCT Effective: - 9.1 dB (CrI: -14.5, -3.2)

TT & Moderate Consistent Somewhat Mix of Moderate 6 RCT

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Key Question or Population

Outcome Comparison Risk of Bias for the evidence-base

Consistency Precision Directness Overall Rating

Key Findings and Comments

Adenoidectomy vs. Watchful waiting

to high imprecise direct and indirect from network MA

Effective: -10.3 dB (CrI: -18.6, -1.6)

Improvement (decrease) in mean hearing level (12-24 months)

TT vs. Watchful waiting

Moderate to high

Consistent Mostly precise

Mix of direct and indirect from network MA

Moderate 5 RCT Not effective: 0.03 dB (CrI: -3.9, 3.3)

TT & Adenoidectomy vs. Watchful waiting

Moderate to high

Consistent Imprecise Mix of direct and indirect from network MA

Insufficient 5 RCT Possibly effective: -3.8 dB (CrI: -8.5, 0.62

Decrease in mean duration of time with middle ear effusion

TT vs. Watchful waiting

Moderate to high

Consistent Imprecise Mix of direct and indirect from network MA

Insufficient 6 RCT Possibly effective: -17 weeks (CrI: -40.0, 4.9)

TT & Adenoidectomy vs. Watchful waiting

Moderate to high

Consistent Imprecise Mix of direct and indirect from network MA

Insufficient 6 RCT Possibly effective: -23 weeks (CrI: -56.0, 9.9)

Quality of life and patient –centered outcomes

TT vs Watchful waiting

Low to moderate

Consistent Imprecise Direct Low 5 RCTs, 3 NRCSs Not effective Multiple outcomes No quantitative synthesis done

Hearing test as a modifier of effectiveness

Moderate to high

Unknown Imprecise Direct Insufficient No quantitative synthesis done

Other patient factors which modify effectiveness of TT

Moderate to high

Unknown Imprecise Direct Insufficient No quantitative synthesis Sparse reporting of potential predictors

Separately for populations at

various High Inconsistent Imprecise Direct Insufficient No RCTs 6 NRCSs

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Key Question or Population

Outcome Comparison Risk of Bias for the evidence-base

Consistency Precision Directness Overall Rating

Key Findings and Comments

high risk (e.g. cleft palate, Down syndrome) Key Question 2 Tympanostomy tubes in children with recurrent AOM

TT vs. Watchful waiting

High Consistent Imprecise Direct Low 6 RCTs (1049 patients) No quantitative synthesis Magnitude of clinically important effects unclear

TT vs. TT & Adenoidectomy

Moderate to high

Consistent Imprecise Direct Low 3 RCTs No quantitative synthesis

Quality of Life

TT vs. Watchful waiting

Moderate NA Imprecise Direct Low 1 RCT

Factors which identify children most likely to benefit

TT vs. Watchful waiting

High Unknown Imprecise Indirect Insufficient

Key Question 4 Ear plugs or water restrictions in children with TT

Average rate of otorrhea

Ear plugs vs. no precautions

Moderate NA Imprecise Direct Low Possibly effective Single RCT Magnitude of clinically important effects unclear

Nonswimming vs. no precautions

High NA Imprecise Direct Low No effect Single RCT

Risk of one or more episodes of otorrhea

Ear plugs vs. no precautions

High Consistent Imprecise Direct Low Not effective 4 NRCSs OR 1.7 (CrI: 0.9, 3.1)

Nonswimming vs. no precautions

High Mostly consistent

Imprecise Direct Low Not effective 6 NRCSs OR 1.52 (CrI: 0.7, 3.2)

Key Question 5 Treatment of TT otorrhea

Topical antibiotic-

Moderate Consistent Somewhat imprecise

Mix of direct

Moderate Network MA of 7

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Key Question or Population

Outcome Comparison Risk of Bias for the evidence-base

Consistency Precision Directness Overall Rating

Key Findings and Comments

glucocorticoid drops vs. watchful waiting

and indirect from network MA

studies Effective: OR 12.0 (CrI: 1.9, 82.0)

Topical antibiotic drops vs watchful waiting

Moderate Consistent Somewhat imprecise

Mix of direct and indirect from network MA

Moderate Network MA of 7 studies Effective: OR 7.2 (CrI: 1.2, 51.0)

Topical antibiotic-glucocorticoid drops vs. oral antibiotics

Moderate Consistent Somewhat imprecise

Mix of direct and indirect from network MA

Moderate Network MA of 10 studies Effective: OR 5.3 (CrI: 1.2, 27.0)

Topical antibiotic vs. oral antibiotics

Moderate Consistent Imprecise Mix of direct and indirect from network MA

Insufficient Network MA of 10 studies OR 3.3 (CrI: 0.75, 16.0)

Quality of Life

Moderate NA Imprecise Direct Insufficient Single RCT

CrI= Credibility Interval; MA = meta-analysis; OR = odds ratio; dB = decibel, MEE= middle ear effusion; TT=Tympanostomy Tubes; MEE= Middle Ear Effusion; RCT= Randomized Control Trial, NRCS=Nonrandomized Comparative Study

Limitations The available evidence base is composed of studies that evaluate multiple interventions.

Several of these, such as myringotomy alone and oral antibiotic prophylaxis, are rarely used in current practice. Thus, the direct evidence relating to the comparisons of interest must rely on a smaller subset of studies or be augmented with indirect evidence from network meta-analysis.

Many of these trials were performed prior to widespread use of conjugate pneumococcal vaccines and in an era where antibiotic resistance was less common. It is unclear whether these or other factors affect the relative (current vs. historical) benefits of TT placement for recurrent AOM.

With the exception of two trials 36, 49 that included children with chronic MEE or recurrent AOM, most enrolled predominately children with chronic MEE. The degree to which patients in clinical practice may have both chronic MEE and recurrent AOM is unclear.

In general, individual studies did not explore treatment effect heterogeneity across subgroups of children by age, sex, clinical history, or sociodemographic factors. Further, we were not able to conduct meaningful subgroup analyses across studies, because most trials used similar inclusion criteria, and thus were not highly variable in terms of the proportions of age, sex,

50

clinical indications, or other baseline characteristics, and because reporting of information on sociodemographic risk factors was sparse and inconsistent.

The generalizability of results to infants and young toddlers and to school age children is also uncertain, given that children in these age groups are underrepresented in available trials.

With the exception of a few NRCSs, patients with cleft palate and Down syndrome have been systematically excluded from comparative trials, limiting the applicability of the evidence for these and other similar subgroups, who experience a higher burden of middle ear disease. Similarly, patients at increased risk of developmental or behavioral sequelae from middle ear disease have not been included (or at least identified) in trials to date.

Across RCTs included in KQs 1 and 2, there was universal lack of blinding of participants, and in many cases of outcome assessors, suggesting a higher risk for ascertainment (measurement) bias, especially for subjective, patient-reported outcomes. Given the intervention in question, placement of a tube in a visible anatomic structure, blinding of participants is not easily accomplished. In addition many studies are at risk for attrition bias, due to dropouts and incomplete followup.

Our meta-analysis of hearing levels used average pure tone hearing levels (typically reported as an average over frequencies of 500, 1000, 2000 and 4000 Hz). This simple measurement is likely insufficient to fully elucidate the complex relationships between hearing and speech perception and development in children.

Assessment of the effectiveness of TT in children with recurrent acute otitis media is particularly challenging, since an episode of AOM in control children (with intact tympanic membrane) results in otalgia and inflammatory changes, whereas children with a functioning TT may present with varying degrees of otorrhea. Bacterial cultures performed in the setting of research may assist in differentiating infections due to organisms associated with AOM from superinfections or colonization with other organisms (e.g. Staphylococcus or Pseudomonas species). Intermediate, outcomes which rely on simple counts or rates of otorrhea, fail to account for the variable character of otorrhea with respect to duration, character, and patient impact. For example, otorrhea may be transient (of little to no concern), recurrent (of more concern, but usually readily managed), or chronic (of considerable concern and difficult to manage).

Our network meta-analysis of the effectiveness of treatments for otorrhea combines trials of fluoroquinolones with other non FDA approved preparations. This presumes equivalent effectiveness and does not consider variable side effects, such as ototoxicity, which may be associated with some agents.

Future Research Recommendations Current indications for TT placement largely reflect the inclusion criteria used in clinical

trials. Well-validated prognostic models are urgently needed to further stratify the risk of individual children with regard to persistence of middle ear effusion or recurrent AOM.

Pragmatic trials are needed, particularly in children with recurrent AOM, but also in children with chronic MEE or some combination of both. There should be an emphasis on exploring treatment effect heterogeneity, i.e. differential effects of interventions in populations at different risk levels for outcomes of interest. Of specific interest is information on the effects of interventions among higher risk groups, such as patients with cleft palate, Down syndrome, and children with neurodevelopmental disorders.

Since TTs are no longer effective after extrusion, future trials should record per-ear and per-patient outcomes conditional on whether the TT has been extruded and conduct appropriate

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analyses to estimate the causal effects of TTs among children who still have TTs in place. An analogous observation is that, in trials comparing nonsurgical and surgical interventions, interpretation of findings by intention to treat analyses are often complicated by the high cross-over rates from nonsurgical interventions, such as watchful waiting to surgical ones such as TTs.

Outcome assessment in children with recurrent acute otitis media is challenging, since an episode of AOM in children with an intact tympanic membrane results in otalgia and inflammatory changes, whereas children with a functioning TT exhibit otorrhea. Reliance on outcomes based on simple counts or rates of otorrhea fail to account for the variable character of otorrhea, which can be transient (of little to no concern), recurrent (of more concern, but usually readily managed), or chronic (of considerable concern and difficult to manage). Future trials would benefit from standardization and consistent definition of adverse events. In some cases, e.g. premature extrusion, one author’s premature extrusion may be another’s time extrusion, depending on the duration of anticipated need.204

Bacteriologic evaluations performed in the research setting may assist in differentiating otorrhea resulting from infection with organisms associated with AOM (e.g. Streptoccus pneumoniae, nontypable Haemophilus influenza) from superinfections with organisms associated with chronic otorrhea (e.g. Staphylococcus aureus and Pseudomonas aeruginosa).205

Conclusions Overall, the evidence suggests that TT placed in children with persistent middle-ear effusion

result in short term improvements in hearing compared to watchful waiting. However, there is no evidence of a sustained benefit.

Our network meta-analysis of hearing thresholds suggests the possibility of a more sustained improvement in hearing thresholds in at least some children who undergo adenoidectomy and TT placement. A nuanced understanding of which children may benefit from adenoidectomy is limited by the small evidence base and our use of aggregate data.

The evidence suggests that TT did not improve cognition, behavior, or quality of life. However, the evidence if sparse, and prevents any definitive conclusions. The results apply to otherwise healthy children without baseline disorders or delays in language, cognition, or and provide little guidance for the treatment of children who may be at increased risk for speech, language, or learning problems because of baseline sensory, physical, cognitive or behavioral factors.

Children with recurrent AOM may have fewer episodes after TT placement, but the evidence base is severely limited. It is unclear whether quality of life outcomes are improved. The benefits of TT placement must be weighed against a variety of adverse events associated with TT placement.

In children in whom TT have been placed, there is no compelling evidence for the need to either avoid swimming or bathing or use ear plugs or bathing caps

Should otorrhea develop, the available evidence supports treatment of TT otorrhea with a topical antibiotic or antibiotic-glucocorticoid drop.

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146. Paradise JL, Bluestone CD, Rogers KD, et al. Efficacy of adenoidectomy for recurrent otitis media in children previously treated with tympanostomy-tube placement. Results of parallel randomized and nonrandomized trials. JAMA. 1990 Apr 18;263(15):2066-73. PMID: 2181158.

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163. De Beer BA, Schilder AG, Zielhuis GA, et al. Natural course of tympanic membrane pathology related to otitis media and ventilation tubes between ages 8 and 18 years. Otol Neurotol. 2005 Sep;26(5):1016-21. PMID: 16151352.

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165. Florentzson R, Finizia C. Transmyringeal ventilation tube treatment: a 10-year cohort study. Int J Pediatr Otorhinolaryngol. 2012 Aug;76(8):1117-22. doi: 10.1016/j.ijporl.2012.04.013. PMID: 22648089.

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166. O'Niel MB, Cassidy LD, Link TR, et al. Tracking tympanostomy tube outcomes in pediatric patients with otitis media using an electronic database. Int J Pediatr Otorhinolaryngol. 2015 Aug;79(8):1275-8. doi: 10.1016/j.ijporl.2015.05.029. PMID: 26115935.

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169. Slack RW, Maw AR, Capper JW, et al. Prospective study of tympanosclerosis developing after grommet insertion. J Laryngol Otol. 1984 Aug;98(8):771-4. PMID: 6470572.

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171. Koc A, Uneri C. Sex distribution in children with tympanosclerosis after insertion of a tympanostomy tube. Eur Arch Otorhinolaryngol. 2001 Jan;258(1):16-9. PMID: 11271428.

172. Friedman EM, Sprecher RC, Simon S, et al. Quantitation and prevalence of tympanosclerosis in a pediatric otolaryngology clinic. Int J Pediatr Otorhinolaryngol. 2001 Sep 28;60(3):205-11. PMID: 11551611.

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174. Bonding P, Lorenzen E. Cicatricial changes of the eardrum after treatment with grommets. Acta Otolaryngol. 1973 Apr;75(4):275-6. PMID: 4702615.

175. Li Y, Hunter LL, Margolis RH, et al. Prospective study of tympanic membrane retraction, hearing loss, and multifrequency tympanometry. Otolaryngol Head Neck Surg. 1999 Nov;121(5):514-22. PMID: 10547462.

176. Tos M, Poulsen G. Attic retractions following secretory otitis. Acta Otolaryngol. 1980 May-Jun;89(5-6):479-86. PMID: 7192477.

177. Golz A, Goldenberg D, Netzer A, et al. Cholesteatomas associated with ventilation tube insertion. Arch Otolaryngol Head Neck Surg. 1999 Jul;125(7):754-7. PMID: 10406312.

178. Spilsbury K, Ha JF, Semmens JB, et al. Cholesteatoma in cleft lip and palate: a population-based follow-up study of children after ventilation tubes. Laryngoscope. 2013 Aug;123(8):2024-9. doi: 10.1002/lary.23753. PMID: 23737350.

179. Djurhuus BD, Christensen K, Skytthe A, et al. The impact of ventilation tubes in otitis media on the risk of cholesteatoma on a national level. Int J Pediatr Otorhinolaryngol. 2015 Apr;79(4):605-9. doi: 10.1016/j.ijporl.2015.02.005. PMID: 25724629.

180. Goldstein NA, Mandel EM, Kurs-Lasky M, et al. Water precautions and tympanostomy tubes: a randomized, controlled trial. Laryngoscope. 2005 Feb;115(2):324-30. doi: 10.1097/01.mlg.0000154742.33067.fb. PMID: 15689760.

181. Parker GS, Tami TA, Maddox MR, et al. The effect of water exposure after tympanostomy tube insertion. Am J Otolaryngol. 1994 May-Jun;15(3):193-6. PMID: 8024107.

182. Becker GD, Eckberg TJ, Goldware RR. Swimming and tympanostomy tubes: a prospective study. Laryngoscope. 1987 Jun;97(6):740-1. PMID: 3586818.

183. Cohen HA, Kauschansky A, Ashkenasi A, et al. Swimming and grommets. J Fam Pract. 1994 Jan;38(1):30-2. PMID: 8289048.

184. el Silimy O, Bradley PJ. Bacteriological aspects of swimming with grommets. Clin Otolaryngol Allied Sci. 1986 Oct;11(5):323-7. PMID: 3780019.

185. Francois M, Jaquemin P, Margo JN, et al. [Swimming and ventilating tubes. Results of a multicenter study]. Ann Pediatr (Paris). 1992 Dec;39(10):627-9. PMID: 1485779.

186. Kaufmann TU, Veraguth D, Linder TE. [Water precautions after insertion of a tympanostomy tube: necessary or obsolete?]. Schweiz Med Wochenschr. 1999 Oct 9;129(40):1450-5. PMID: 10546304.

187. Salata JA, Derkay CS. Water precautions in children with tympanostomy tubes. Arch Otolaryngol Head Neck Surg. 1996 Mar;122(3):276-80. PMID: 8607955.

62

188. Sharma PD. Swimming with grommets. Scand Audiol Suppl. 1986;26:89-91. PMID: 3472335.

189. Smelt GJ, Yeoh LH. Swimming and grommets. J Laryngol Otol. 1984 Mar;98(3):243-5. PMID: 6538215.

190. Konradsson K, Ortegren U. [Transmyringeal ventilation tubes: postoperative restrictions and early complications]. Lakartidningen. 1986 Oct 15;83(42):3514-7. PMID: 3784716.

191. Waycaster C, Cockrum P, Reese B, et al. Treatment of Acute Otitis Media in Children with Tympanostomy Tubes: A Caregiver's Perspective. Pharmacy and Therapeutics. 2004;29(11):721-30.

192. Goldblatt EL, Dohar J, Nozza RJ, et al. Topical ofloxacin versus systemic amoxicillin/clavulanate in purulent otorrhea in children with tympanostomy tubes. Int J Pediatr Otorhinolaryngol. 1998 Nov 15;46(1-2):91-101. PMID: 10190709.

193. Ruohola A, Heikkinen T, Jero J, et al. Oral prednisolone is an effective adjuvant therapy for acute otitis media with discharge through tympanostomy tubes. J Pediatr. 1999 Apr;134(4):459-63. PMID: 10190921.

194. Dohar JE, Garner ET, Nielsen RW, et al. Topical ofloxacin treatment of otorrhea in children with tympanostomy tubes. Arch Otolaryngol Head Neck Surg. 1999 May;125(5):537-45. PMID: 10326811.

195. Ruohola A, Heikkinen T, Meurman O, et al. Antibiotic treatment of acute otorrhea through tympanostomy tube: randomized double-blind placebo-controlled study with daily follow-up. Pediatrics. 2003 May;111(5 Pt 1):1061-7. PMID: 12728089.

196. Roland PS, Anon JB, Moe RD, et al. Topical ciprofloxacin/dexamethasone is superior to ciprofloxacin alone in pediatric patients with acute otitis media and otorrhea through tympanostomy tubes. Laryngoscope. 2003 Dec;113(12):2116-22. doi: 10.1097/00005537-200312000-00011. PMID: 14660913.

197. Granath A, Rynnel-Dagoo B, Backheden M, et al. Tube associated otorrhea in children with recurrent acute otitis media; results of a prospective randomized study on bacteriology and topical treatment with or without systemic antibiotics. Int J Pediatr Otorhinolaryngol. 2008 Aug;72(8):1225-33. doi: 10.1016/j.ijporl.2008.04.015. PMID: 18565598.

198. Heslop A, Lildholdt T, Gammelgaard N, et al. Topical ciprofloxacin is superior to topical saline and systemic antibiotics in the treatment of tympanostomy tube otorrhea in children: the results of a randomized clinical trial. Laryngoscope. 2010 Dec;120(12):2516-20. doi: 10.1002/lary.21015. PMID: 20979100.

199. van Dongen TM, van der Heijden GJ, Venekamp RP, et al. A trial of treatment for acute otorrhea in children with tympanostomy tubes. N Engl J Med. 2014 Feb 20;370(8):723-33. doi: 10.1056/NEJMoa1301630. PMID: 24552319.

200. van Dongen TM, Venekamp RP, Wensing AM, et al. Acute otorrhea in children with tympanostomy tubes: prevalence of bacteria and viruses in the post-pneumococcal conjugate vaccine era. Pediatr Infect Dis J. 2015 Apr;34(4):355-60. doi: 10.1097/inf.0000000000000595. PMID: 25764097.

201. Roland PS, Dohar JE, Lanier BJ, et al. Topical ciprofloxacin/dexamethasone otic suspension is superior to ofloxacin otic solution in the treatment of granulation tissue in children with acute otitis media with otorrhea through tympanostomy tubes. Otolaryngol Head Neck Surg. 2004 Jun;130(6):736-41. doi: 10.1016/j.otohns.2004.02.037. PMID: 15195060.

202. Strachan D, Clarke SE, England RJ. The effectiveness of topical treatment in discharging ears with in-dwelling ventilation tubes. Rev Laryngol Otol Rhinol (Bord). 2000;121(1):27-9. PMID: 10865480.

203. Rovers MM, Black N, Browning GG, et al. Grommets in otitis media with effusion: an individual patient data meta-analysis. Arch Dis Child. 2005 May;90(5):480-5. doi: 10.1136/adc.2004.059444. PMID: 15851429.

204. Kay DJ, Nelson M, Rosenfeld RM. Meta-analysis of tympanostomy tube sequelae. Otolaryngol Head Neck Surg. 2001 Apr;124(4):374-80. PMID: 11283489.

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205. Idicula WK, Jurcisek JA, Cass ND, et al. Identification of biofilms in post-tympanostomy tube otorrhea. Laryngoscope. 2016 Aug;126(8):1946-51. doi: 10.1002/lary.25826. PMID: 27426942.

64

Appendix A. Literature Search

MEDLINE (5/19/16, 6553 Citations) ((otitis) OR (“glue ear”) OR "Otitis Media with Effusion"[Mesh] OR "Otitis Media, Suppurative"[Mesh] OR "Ear, Middle/secretion"[Mesh] OR (middle and ear and (effusion* or infect* or inflame* or disease*)) OR ((OME OR SOM or AOM) AND (otitis OR ear)) OR ((mucoid* AND middle AND ear) OR (mucous AND middle AND ear) OR (seromuc* AND middle AND ear))) AND (tympanostomy OR grommet* OR ((ear or “pressure equalization” or PE or myringotomy or ventilating or ventilation) and (tube or tubes)) OR “Otitis Media with Effusion/surgery”[mesh] OR "Middle Ear Ventilation"[Mesh] OR ((middle AND (ear OR tympanic)) AND (tube or tubes)) OR "Otologic Surgical Procedures"[Mesh] OR T-tube or tabulation)

COCHRANE (5/19/16, 393 Citations) ((otitis) OR (“glue ear”) OR [mh “Otitis Media with Effusion”] OR [mh “Otitis Media, Suppurative”] OR [mh “Ear, Middle/secretion”] OR (middle and ear and (effusion* or infect* or inflame* or disease*)) OR ((OME OR SOM or AOM) AND (otitis OR ear)) OR ((mucoid* AND middle AND ear) OR (mucous AND middle AND ear) OR (seromuc* AND middle AND ear))) AND (tympanostomy OR grommet* OR ((ear or “pressure equalization” or PE or myringotomy or ventilating or ventilation) and (tube or tubes)) OR [mh “Otitis Media with Effusion/surgery”] OR [mh "Middle Ear Ventilation"] OR ((middle AND (ear OR tympanic)) AND (tube or tubes)) OR [mh “Otologic Surgical Procedures"] OR T-tube or tabulation)

CINAHL (5/19/16, 852 Citations) ((MH "Otitis") OR (MH "Otitis Media with Effusion") OR (MH "Otitis Media") OR otitis OR (“glue ear”) OR (MH "Ear, Middle") OR (middle and ear and (effusion* or infect* or inflame* or disease*)) OR ((OME OR SOM or AOM) AND (otitis OR ear)) OR ((mucoid* AND middle AND ear) OR (mucous AND middle AND ear) OR (seromuc* AND middle AND ear))) AND (tympanostomy or myringotomy OR (MH "Middle Ear Ventilation") OR grommet* OR ((ear or “pressure equalization” or PE or myringotomy or ventilating or ventilation) and (tube or tubes)) OR ((middle AND (ear OR tympanic)) AND (tube or tubes)) OR (MH "Ear Surgery") OR T-tube or tabulation)

A-1

EMBASE (5/19/16, 5556 Citations) (otitis OR 'otitis media'/exp OR glue ear OR (middle and ear and (effusion* or infect* or inflame* or disease*)) OR ((OME OR SOM or AOM) AND (otitis OR ear)) OR ((mucoid* AND middle AND ear) OR (mucous AND middle AND ear) OR (seromuc* AND middle AND ear))) AND (tympanostomy OR 'tympanostomy tube'/exp OR 'myringotomy'/exp OR 'middle ear ventilation'/exp OR grommet* OR ((ear or “pressure equalization” or PE or myringotomy or ventilating or ventilation) and (tube or tubes)) OR ((middle AND (ear OR tympanic)) AND (tube or tubes)) OR T-tube or tabulation)

A-2

Appendix B. Excluded Studies

Table B1. Excluded studies

PMID Author(s) Title Journal Exclusion Reason

Diacova S. and Desvignes V. and Chiaburu A. and Chirtoca D. and Parii S.

Tympanostomy and adenoidectomy for treatment of otitis media in children

Archives of Disease in Childhood (2012) 97 SUPPL. 2 (A453). Date of Publication: October 2012

Abstract

Cheng L. and Chen S. and Cheng J.

Does tube type matter in posttympanostomy tube otorrhea?

Otolaryngology - Head and Neck Surgery (United States) (2014) 151:1 SUPPL. 1 (P147). Date of Publication: September 2014

Abstract

Chen S. and Cheng L. and Chen T. and Cheng J. and Cheng R. and Cheng D.

A review of 2399 ears for postmyringotomy tube otorrhea

Otolaryngology - Head and Neck Surgery (United States) (2012) 147 SUPPL. 2 (P130-P131). Date of Publication: August 2012

Abstract

Wang M.-C. Ventilation tube insertions for pediatric otitis media with effusion: With adenoidectomy or not

Otolaryngology - Head and Neck Surgery (2011) 145 SUPPL. 2 (114). Date of Publication: August 2011

Abstract

Russell C. and Black O. and Dutt D. and Ray A. and Devlin M. and Wynne D.

Are ventilation tubes (grommets) in cleft children truly associated with increased complication rates? Results of a nested case control study of cleft and non-cleft children

British Journal of Oral and Maxillofacial Surgery (2012) 50 SUPPL. 1 (S2-S3). Date of Publication: June 2012

Abstract

Sidell D.R. and Hunter L. and Lin L. and Arjmand E.M.

Risk factors for hearing loss in the setting of pressure equalization tube placement in children

Otolaryngology - Head and Neck Surgery (United States) (2013) 149:2 SUPPL. 1 (P122). Date of Publication: September 2013

Abstract

Black O. and Dutt D. and Russell C. and Devlin M. and Ray A. and Wynne D.

Ventilation tubes in cleft children carry no higher risk of complication than their use in non cleft children: Results of a nested case control study

Clinical Otolaryngology (2012) 37 SUPPL. 1 (181-182). Date of Publication: July 2012 Abstract

Wolter N.E. and Dell S. and James A.L. and Campisi P.

Middle ear ventilation in children with primary ciliary dyskinesia

Otolaryngology - Head and Neck Surgery (2011) 145 SUPPL. 2 (111). Date of Publication: August 2011

Abstract

Diacova S. and Ababii I. and Maniuc M. and Danilov L. and Ababii P. and Diacova O. and McDonald T.J.

Modified surgery in children with persistent and recurrent otitis media

Archives of Disease in Childhood (2014) 99 SUPPL. 2 (A137). Date of Publication: October 2014

Abstract

Sobin, L. B. and Imbery, T. E. and Tatum, S. A. and Nicholas, B. D. and Koester, L.

Long-term otologic outcomes in patients with cleft palates Abstract

B-1

PMID Author(s) Title Journal Exclusion Reason

5567839 J K Graham Serous otitis media: complication of polyethylene tube insertion Eye, ear, nose & throat monthly Case report

12610892 Pulec J.L. and Deguine C. Long-term ventilating tube with tympanosclerosis

Ear, Nose and Throat Journal (2003) 82:1 (8). Date of Publication: 1 Jan 2003 Case report

11011482 Pulec J.L. and Deguine C. Long-term ventilating tube with tympanosclerosis

Ear, Nose and Throat Journal (2000) 79:9 (680). Date of Publication: 2000 Case report

13157738 Armstrong B.W. A new treatment for chronic secretory otitis media

Archives of otolaryngology (1954) 59:6 (653-654). Date of Publication: 1954 Case report

5081036 Gulzow J. Observations during long-term drainage of the middle ear in chronic catarrh of the eustachian tube

Zeitschrift fur Laryngologie, Rhinologie, Otologie und ihre Grenzgebiete (1972) 51:10 (665-670). Date of Publication: Oct 1972

Case report

10624048 Deguine C. and Pulec J.L. Grommet ventilation myringostomy with cholesteatoma

Ear, Nose and Throat Journal (1999) 78:12 (884). Date of Publication: 1999 Case report

18357935 Abbarah T. and Abbarah M.A. Migration of T-tubes to the middle ear Ear, Nose and Throat Journal (2008) 87:1. Date of Publication: January 2008 Case report

16406076 Riccardo D'Eredita and Udayan K Shah

Contact diode laser myringotomy for medium-duration middle ear ventilation in children

International journal of pediatric otorhinolaryngology Cohort, N < 50

3218926 C C Lau and K K Loh and N Kunaratnam

Middle ear diseases in cleft palate patients in Singapore

Annals of the Academy of Medicine, Singapore Cohort, N < 50

5778864 J H Per-Lee Experiences with a "permanent" wide flange middle ear ventilation tube The Laryngoscope Cohort, N < 50

17440366 Mohamed E Hassan and Sherif Askar

Does palatal muscle reconstruction affect the functional outcome of cleft palate surgery?

Plastic and reconstructive surgery Cohort, N < 50

9041283 M N Orlin and S K Effgen and S D Handler

Effect of otitis media with effusion on gross motor ability in preschool-aged children: preliminary findings

Pediatrics Cohort, N < 50

7619414 R W Force and M C Hart and S A Plummer and D A Powell and M C Nahata

Topical ciprofloxacin for otorrhea after tympanostomy tube placement

Archives of otolaryngology--head & neck surgery Cohort, N < 50

6023618 W L Draper Secretory otitis media in children: a study of 540 children The Laryngoscope Cohort, N < 50

8504893 M Selikowitz Short-term efficacy of tympanostomy tubes for secretory otitis media in children with Down syndrome

Developmental medicine and child neurology Cohort, N < 50

8551144 D P Martin-Hirsch and C J Woodhead and C E Vize

Long-term ventilation of the middle ear using a tympanotomy technique The Journal of laryngology and otology Cohort, N < 50

B-2

PMID Author(s) Title Journal Exclusion Reason

10504021 Y Iino and Y Imamura and S Harigai and Y Tanaka

Efficacy of tympanostomy tube insertion for otitis media with effusion in children with Down syndrome

International journal of pediatric otorhinolaryngology Cohort, N < 50

3444993 B Pérez Piñero and D López Aguado and M E Campos Bañales [Tympanosclerosis and the ventilation tube] Revue de laryngologie - otologie - rhinologie Cohort, N < 50

7818639 J G Gilbert Swimming and grommets: a prospective survey The New Zealand medical journal Cohort, N < 50

7861292 S Harigai [Longitudinal studies in hearing-impaired children with Down's syndrome] Nihon Jibiinkoka Gakkai kaiho Cohort, N < 50

14823225 {CHAUVET} [Consideration on the therapy of tubal otorrhea] Gazette médicale de France Cohort, N < 50

1742892 P J Dawes and B J Bingham and R Rhys and M V Griffiths

Aspirating middle ear effusions when inserting ventilation tubes: does it influence post-operative otorrhoea, tube obstruction or the development of tympanosclerosis?

Clinical otolaryngology and allied sciences Cohort, N < 50

19251534 Mao-Che Wang and Chia-Yu Liu and An-Suey Shiao

Water penetration into middle ear through ventilation tubes in children while swimming

Journal of the Chinese Medical Association : JCMA Cohort, N < 50

3418217 C Watson and K S Mangat A comparison of audiometric performance and complications of T tubes and Shepard grommets

The Journal of laryngology and otology Cohort, N < 50

512469 J Samuel and G Rosen and Y Vered

Use of middle ear ventilation tubes in recurrent acute otitis media The Journal of laryngology and otology Cohort, N < 50

2769837 D McRae and D J Gatland and R Youngs and J Cook

Aspiration of middle ear effusions prior to grommet insertion an etiological factor in tympanosclerosis

The Journal of otolaryngology Cohort, N < 50

3427802 E Chevretton and B J Bingham and E Firman

The prevention of tympanic membrane perforation following the removal of long-term Paparella type II ventilation tubes

Clinical otolaryngology and allied sciences Cohort, N < 50

3243014 T H Lesser and K R Williams and D W Skinner

Tympanosclerosis, grommets and shear stresses Clinical otolaryngology and allied sciences Cohort, N < 50

4855092 H L Wilson The steel whisker tube in chronic secretory otitis media

Transactions - American Academy of Ophthalmology and Otolaryngology. American Academy of Ophthalmology and Otolaryngology

Cohort, N < 50

5550610 N Shah Use of grommets in 'glue' ears The Journal of laryngology and otology Cohort, N < 50

22796197 Tuomas Klockars and Jorma Rautio Early placement of ventilation tubes in cleft lip and palate patients: does palatal closure affect tube occlusion and short-term

International journal of pediatric otorhinolaryngology Cohort, N < 50

B-3

PMID Author(s) Title Journal Exclusion Reason

outcome?

1863436 H C Pillsbury and J H Grose and J W Hall

Otitis media with effusion in children. Binaural hearing before and after corrective surgery

Archives of otolaryngology--head & neck surgery Cohort, N < 50

14568787

Joseph W Hall and John H Grose and Emily Buss and Madhu B Dev and Amelia F Drake and Harold C Pillsbury

The effect of otitis media with effusion on perceptual masking

Archives of otolaryngology--head & neck surgery Cohort, N < 50

7190178 Q Bailey The Castelli membrane in the treatment of glue ear The Journal of laryngology and otology Cohort, N < 50

18072559

Wei Li and Wei Shang and Ai-hua Yu and Xiao-heng Zhang and Yu-xin Liu and Xiu-ming Wan and Mu-yun Jia and Ning-yi Li

[Early treatment of middle ear disease in cleft palate infants]

Hua xi kou qiang yi xue za zhi = Huaxi kouqiang yixue zazhi = West China journal of stomatology

Cohort, N < 50

26949997 Nihat Kılıç and Özgür Yörük and Songül Cömert Kılıç and Gülhan Çatal and Sezgin Kurt

Rapid maxillary expansion versus middle ear tube placement:Comparison of hearing improvements in children with resistance otitis media with effusion

Mar Cohort, N < 50

2492178 G A Gates and C A Avery and J C Cooper and T J Prihoda

Chronic secretory otitis media: effects of surgical management

The Annals of otology, rhinology & laryngology. Supplement

No extractable data

4040338 G A Gates and C Wachtendorf and E M Hearne and G R Holt

Treatment of chronic otitis media with effusion: results of tympanostomy tubes American journal of otolaryngology No extractable

data

3336263 G A Gates and C A Avery and T J Prihoda

Effect of adenoidectomy upon children with chronic otitis media with effusion The Laryngoscope No extractable

data

11678951 {Medical Research Council Multicentre Otitis Media Study Group}

Surgery for persistent otitis media with effusion: generalizability of results from the UK trial (TARGET). Trial of Alternative Regimens in Glue Ear Treatment

Clinical otolaryngology and allied sciences No extractable data

11434951 M M Rovers and G A Zielhuis and K Bennett and M Haggard

Generalisability of clinical trials in otitis media with effusion

International journal of pediatric otorhinolaryngology

No extractable data

18685496 {MRC Multicentre Otitis Media Study Group}

An extension of the Jerger classification of tympanograms for ventilation tube patency--specification and evaluation of equivalent ear-canal volume criteria

Ear and hearing No extractable data

12363423 A A Maheshwar and M A P Milling and M Kumar and M I Clayton and A Thomas

Use of hearing aids in the management of children with cleft palate

International journal of pediatric otorhinolaryngology

No extractable data

25677370 Joong Ho Ahn and Woo Seok Kang Critical reassessment of the probability of Acta oto-laryngologica No extractable

B-4

PMID Author(s) Title Journal Exclusion Reason

and Ji Heui Kim and Kyung S Koh and Tae Hyun Yoon

receiving additional ventilation tube insertion for recurrent otitis media with effusion in children with a cleft palate

data

3818186 H Hafner and I Anteby and H Pratt and M Goldsher and R Shenhav and H Z Joachims

Auditory brainstem evoked potentials in evaluating the efficacy of surgical ventilation of the middle ear

International journal of pediatric otorhinolaryngology

No extractable data

10542923 J D Hern and D A Jonathan Insertion of ventilation tubes: does the site matter? Clinical otolaryngology and allied sciences No extractable

data

8741962 L L Hunter and R H Margolis and J R Rykken and C T Le and K A Daly and G S Giebink

High frequency hearing loss associated with otitis media Ear and hearing No extractable

data

3818185 I Anteby and H Hafner and H Pratt and N Uri

Auditory brainstem evoked potentials in evaluating the central effects of middle ear effusion

International journal of pediatric otorhinolaryngology

No extractable data

6778358 B Hussl and K Welzl-Mueller Secretory otitis media and mastoid pneumatization

The Annals of otology, rhinology & laryngology. Supplement

No extractable data

24243868

Christina T Ryborg and Jens Søndergaard and Jørgen Lous and Anders Munck and Pia V Larsen and Janus L Thomsen

Quality of life in children with otitis media--a cohort study Family practice No extractable

data

11074114 Y Rakover and K Keywan and G Rosen

Comparison of the incidence of cholesteatoma surgery before and after using ventilation tubes for secretory otitis media

International journal of pediatric otorhinolaryngology

No extractable data

5795401 Paradise J.L. and Bluestone C.D. and Felder H.

The universality of otitis media in 50 infants with cleft palate

Pediatrics (1969) 44:1 (463-471). Date of Publication: 1969

No extractable data

Morales D.S.R. and Testa J.R.G. and Guilherme A. and Fukuda Y.

Permanence time of 164 ventilation tympanic tubes in 82 cleft palate pacients

Revista Brasileira de Otorrinolaringologia (2001) 67:1 (22-27). Date of Publication: 2001

No extractable data

22531243

Van Dongen T.M.A. and Schilder A.G.M. and Manders L.A. and Van Der Veen E.L. and Van Der Heijden G.J.M.G.

Good agreement between parents and physician in the assessment of ear discharge in children

Pediatric Infectious Disease Journal (2012) 31:8 (868-869). Date of Publication: August 2012

No extractable data

4666579 King J.T. Modified exploratory ulterior tympanotomy in chronic secretory otitis media in children

Trans. Amer. Acad. Ophthal. Otolaryng. (1972) 76:5 (1292-1295). Date of Publication: 1972

No outcomes of interest

25676152 Christian Hamilton Heidemann and Henrik Hein Lauridsen and Anette Drøhse Kjeldsen and Christian Emil

Quality-of-Life Differences among Diagnostic Subgroups of Children Receiving Ventilating Tubes for Otitis

Oct No outcomes of interest

B-5

PMID Author(s) Title Journal Exclusion Reason

Faber and Eva Charlotte Jung Johansen and Christian Godballe

Media

12622537 Mark Boston and Joe McCook and Bonnie Burke and Craig Derkay

Incidence of and risk factors for additional tympanostomy tube insertion in children

Archives of otolaryngology--head & neck surgery

No outcomes of interest

8877207 A R Maw and R Bawden and L O'Keefe and P Gurr

Does the type of middle ear aspirate have any prognostic significance in otitis media with effusion in children?

Clinical otolaryngology and allied sciences No outcomes of interest

21106257 Richard M Rosenfeld and David W Jang and Konstantin Tarashansky

Tympanostomy tube outcomes in children at-risk and not at-risk for developmental delays

International journal of pediatric otorhinolaryngology

No outcomes of interest

22183901

Nathan S Alexander and Brian D Kulbersh and C Hope Heath and Renee A Desmond and Eric Caron and Audie L Woolley and Jimmy Scott Hill and W Peyton Shirley and Brian J Wiatrak

MRSA and non-MRSA otorrhea in children: a comparative study of clinical course

Archives of otolaryngology--head & neck surgery

No outcomes of interest

12117333 Michele Richards and Carla Giannoni

Quality-of-life outcomes after surgical intervention for otitis media

Archives of otolaryngology--head & neck surgery

No outcomes of interest

12439177 Rahmi Kiliç and Mustafa A Safak and Ali Ozdek and Hakan Göçmen and Dilek Kiliç and Erdal Samim

Effect of 23 valent pneumococcal polysaccharide and Haemophilus influenza conjugated vaccines on the clinical course of otitis media with effusion

The Laryngoscope No outcomes of interest

6539321 O G Neumann and R Laszig [Diagnosis and therapy of seromucous otitis. Experience with 2766 operations on children]

HNO No outcomes of interest

2254809 M Suetake and T Kobayashi and T Takasaka and H Shinkawa

[Middle ear air volume and prognosis of secretory otitis media] Nihon Jibiinkoka Gakkai kaiho No outcomes of

interest

8260856 T C Theoharides and S S Manolidis and H Vliagoftis and L S Manolidis

Treatment of secretory otitis media with local instillation of hydroxyzine

International archives of allergy and immunology

No outcomes of interest

8026089 A R Maw and R Bawden Factors affecting resolution of otitis media with effusion in children Clinical otolaryngology and allied sciences No outcomes of

interest

24983459

Mao-Che Wang and Ying-Piao Wang and Chia-Huei Chu and Tzong-Yang Tu and An-Suey Shiao and Pesus Chou

The protective effect of adenoidectomy on pediatric tympanostomy tube re-insertions: a population-based birth cohort study

PloS one No outcomes of interest

7218998 B F Jaffe Are water and tympanotomy tubes compatible? The Laryngoscope No outcomes of

interest 1787379 A Golz and S T Westerman and L M Effect of middle ear effusion on the The Journal of laryngology and otology No outcomes of

B-6

PMID Author(s) Title Journal Exclusion Reason

Gilbert and H Z Joachims and A Netzer

vestibular labyrinth interest

3974389 B F Lounsbury Swimming unprotected with long-shafted middle ear ventilation tubes The Laryngoscope No outcomes of

interest

9596366 A Golz and B Angel-Yeger and S Parush

Evaluation of balance disturbances in children with middle ear effusion

International journal of pediatric otorhinolaryngology

No outcomes of interest

17645949 Yan Chow and David A M Wabnitz and John Ling

Quality of life outcomes after ventilating tube insertion for otitis media in an Australian population

International journal of pediatric otorhinolaryngology

No outcomes of interest

20504840

Petri S Mattila and Sari Hammarén-Malmi and Harri Saxen and Tarja Kaijalainen and Helena Käyhty and Jussi Tarkkanen

Adenoidectomy and nasopharyngeal carriage of Streptococcus pneumoniae in young children

Archives of disease in childhood No outcomes of interest

7193427 H H Elverland and I W Mair and O K Haugeto and K E Schrøder

Influence of adenoid hypertrophy on secretory otitis media

The Annals of otology, rhinology, and laryngology

No outcomes of interest

23917659 Leticia Reis Borges and Jorge Rizzato Paschoal and Maria Francisca Colella-Santos

(Central) auditory processing: the impact of otitis media Clinics (São Paulo, Brazil) No outcomes of

interest

Donaldson J.A. The role of artificial(bullet) eustaciiian tube in cleft palate patients

Cleft Palate Journal (1966) 3:1 (61-66). Date of Publication: 1966

No outcomes of interest

26218381

Lauren A Hanes and Amanda Murphy and Jill E Hatchette and Raylene Delorey and Kenneth L Wilson and Paul Hong and Michael Bezuhly

Chronic Otitis Media with Effusion Is Associated with Increased Risk of Secondary Speech Surgery

Aug No outcomes of interest

2563465 G A Zielhuis and G H Rach and P van den Broek

Screening for otitis media with effusion in preschool children Lancet (London, England) No outcomes of

interest

1571119 G S Giebink and K Daly and D J Buran and M Satz and T Ayre

Predictors for postoperative otorrhea following tympanostomy tube insertion

Archives of otolaryngology--head & neck surgery

No outcomes of interest

26454528 P Niemi and J Numminen and M Rautiainen and M Helminen and H Vinkka-Puhakka and T Peltomäki

The effect of adenoidectomy on occlusal development and nasal cavity volume in children with recurrent middle ear infection

International journal of pediatric otorhinolaryngology

No outcomes of interest

17403263 S Sood and A Waddell Accurate consent for insertion and later removal of grommets The Journal of laryngology and otology No outcomes of

interest

10208683 C G Gourin and R N Hubbell Otorrhea after insertion of silver oxide-impregnated silastic tympanostomy tubes

Archives of otolaryngology--head & neck surgery

No outcomes of interest

17043261 Erwin L van der Veen and Anne G M Schilder and Niels van Heerbeek

Predictors of chronic suppurative otitis media in children

Archives of otolaryngology--head & neck surgery

No outcomes of interest

B-7

PMID Author(s) Title Journal Exclusion Reason

and Monique Verhoeff and Gerhard A Zielhuis and Maroeska M Rovers

22835927

Petri S Mattila and Sari Hammarén-Malmi and Harri Saxen and Tarja Kaijalainen and Helena Käyhty and Jussi Tarkkanen

Adenoidectomy in young children and serum IgG antibodies to pneumococcal surface protein A and choline binding protein A

International journal of pediatric otorhinolaryngology

No outcomes of interest

14643475 Joseph Dohar Microbiology of otorrhea in children with tympanostomy tubes: implications for therapy

International journal of pediatric otorhinolaryngology

No outcomes of interest

19131420

P S Mattila and S Hammarén-Malmi and A S Pelkonen and L P Malmberg and M J Mäkelä and H Saxen and J Tarkkanen

Effect of adenoidectomy on respiratory function: a randomised prospective study Archives of disease in childhood No outcomes of

interest

3201954 I Augustsson and C Nilsson and P Neander

Do we treat "the right" children with secretory otitis media at the ENT clinic? Acta oto-laryngologica. Supplementum No outcomes of

interest

25764097

Thijs M A van Dongen and Roderick P Venekamp and Annemarie M J Wensing and Debby Bogaert and Elisabeth A M Sanders and Anne G M Schilder

Acute otorrhea in children with tympanostomy tubes: prevalence of bacteria and viruses in the post-pneumococcal conjugate vaccine era

The Pediatric infectious disease journal No outcomes of interest

9176804 Y Rakover and K Keywan and G Rosen

Safety of topical ear drops containing ototoxic antibiotics The Journal of otolaryngology No outcomes of

interest

9288214 H Valtonen and Y Qvarnberg and H Puhakka and J Nuutinen

Early post-tympanostomy otorrhea in children under 17 months of age Acta oto-laryngologica No outcomes of

interest

14740537

Ivan Baljosević and Vladan Subarević and Nikola Mircetić and Jovana Jecmenica and Jovica Karanov and Zorica Vasiljević

[Suppurative middle ear infection as a complication after tympanostomy tube placement]

Medicinski pregled No outcomes of interest

3670236 M Stura and G Ivani [Insertion of trans-tympanic drainage in muco-gelatinous otitis in children] Minerva pediatrica No outcomes of

interest

17178938

David M Poetker and D Richard Lindstrom and Nalin J Patel and Stephen F Conley and Valerie A Flanary and T Roxanne Link and Joseph E Kerschner

Ofloxacin otic drops vs neomycin-polymyxin B otic drops as prophylaxis against early postoperative tympanostomy tube otorrhea

Archives of otolaryngology--head & neck surgery

No outcomes of interest

2128487 K Roos and G Granström and G Karlsson and L Lind and S Olling and U Renvall

Ear discharge after insertion of transmyringeal tubes

International journal of pediatric otorhinolaryngology

No outcomes of interest

12161732 Gordon J Siegel and Rakesh K Laser office ventilation of ears with Otolaryngology--head and neck surgery : No outcomes of

B-8

PMID Author(s) Title Journal Exclusion Reason

Chandra insertion of tubes official journal of American Academy of Otolaryngology-Head and Neck Surgery

interest

5249846 M S Robertson Chronic secretoty otitis media: treatment with trans-tympanic indwelling polythene tubes

The New Zealand medical journal No outcomes of interest

8745020

K A Daly and G S Giebink and B Lindgren and R H Margolis and D Westover and L L Hunter and C T Le and D Buran

Randomized trial of the efficacy of trimethoprim-sulfamethoxazole and prednisone in preventing post-tympanostomy tube morbidity

The Pediatric infectious disease journal No outcomes of interest

16172353 Brechtje de Beer and Ad Snik and Anne G M Schilder and Kees Graamans and Gerhard A Zielhuis

The effect of otitis media in childhood on the development of middle ear admittance on reaching adulthood

Archives of otolaryngology--head & neck surgery

No outcomes of interest

1479274 M A Salam and C Wengraf Glue under pressure: a bad prognostic sign for recurrence of otitis media with effusion The Journal of laryngology and otology No outcomes of

interest

23379112 Min Huang and Sijun Zhao and Yun Li and Xiangyue Peng and Yuting Kuang and Songliang Long

[The effect of tympanostomy tube surgery in cleft palate children with secretory otitis media]

Lin chuang er bi yan hou tou jing wai ke za zhi = Journal of clinical otorhinolaryngology, head, and neck surgery

No outcomes of interest

3713407 G A Gates and C Avery and T J Prihoda and G R Holt Post-tympanostomy otorrhea The Laryngoscope No outcomes of

interest

16510637

Niels van Heerbeek and Masja Straetemans and Selma P Wiertsema and Koen J A O Ingels and Ger T Rijkers and Anne G M Schilder and Elisabeth A M Sanders and Gerhard A Zielhuis

Effect of combined pneumococcal conjugate and polysaccharide vaccination on recurrent otitis media with effusion

Pediatrics No outcomes of interest

Coates H. Preventing and treating grommet tube otorrhoea

Medicine Today (2002) 3:10 (77-79). Date of Publication: 1 Oct 2002

No outcomes of interest

Coates H. and Sashikumar A. A prospective clinical trial of antibiotic/steroid ear drops and incidence of infection following ventilation tube insertion

Journal of the Otolaryngological Society of Australia (1990) 6:4 (272-274). Date of Publication: 1990

No outcomes of interest

Becker C.G. and Da Silva A.L. and Guimaraes R.E.S. and Becker H.M.G. and Barra I.M. and Oliveira W.D.

Surgical treatment of otitis media with effusion: Ventilation tube versus topical application of mitomycin C

Revista Brasileira de Otorrinolaringologia (2003) 69:4 (513-519). Date of Publication: 2003

No outcomes of interest

Raja H. and Williams J. and Tzifa K.

Audiology following up grommets can improve efficiency and finances for ENT

Clinical Otolaryngology (2012) 37 SUPPL. 1 (176). Date of Publication: July 2012

No outcomes of interest

25554572 Axel Håkansson and Rut Florentzson and Lisa Tuomi and Caterina Finizia

Transmyringeal ventilation tube treatment in children: hearing outcome after 10 years Feb No outcomes of

interest

B-9

PMID Author(s) Title Journal Exclusion Reason

26985629 Eric A Mair and Albert H Park and Debra Don and Jeffrey Koempel and Moraye Bear and Carl LeBel

Safety and Efficacy of Intratympanic Ciprofloxacin Otic Suspension in Children With Middle Ear Effusion Undergoing Tympanostomy Tube Placement: Two Randomized Clinical Trials

May No outcomes of interest

26611339

Jacob W Zeiders and Charles A Syms and Mary T Mitskavich and David M Yen and Daniel T Harfe and Ryan D Shields and Brent J Lanier and Andrew R Gould and Jason Mouzakes and C Layton Elliott

Tympanostomy tube placement in awake, unrestrained pediatric patients: A prospective, multicenter study

Dec No outcomes of interest

26454528 P Niemi and J Numminen and M Rautiainen and M Helminen and H Vinkka-Puhakka and T Peltomäki

The effect of adenoidectomy on occlusal development and nasal cavity volume in children with recurrent middle ear infection

Dec No outcomes of interest

11797262 C R Cannon and W H Replogle Otorrhea following Ultracil ear tube insertion

Journal of the Mississippi State Medical Association

No outcomes of interest

3517534 T J Balkany and I K Arenberg and R L Steenerson

Ventilation tube surgery and middle ear irrigation The Laryngoscope No outcomes of

interest

17049144 Marisol Carignan and Dominique Dorion and Marie-France Stephenson and Michel Rouleau

First myringotomy with insertion of a modified Goode T-Tube: changing the perforation paradigm

The Journal of otolaryngology No outcomes of interest

21777983 David M Gleinser and Hilda H Kriel and Shraddha Mukerji

The relationship between repeat tympanostomy tube insertion and adenoidectomy

International journal of pediatric otorhinolaryngology

No outcomes of interest

7550814 D A Clements and L Langdon and C Bland and E Walter

Influenza A vaccine decreases the incidence of otitis media in 6- to 30-month-old children in day care

Archives of pediatrics & adolescent medicine No outcomes of interest

Elverland H.H. and Haugeto O.K. and Andersen L. Adenoidectomy and secretory otitis media Acta Oto-Laryngologica (1982) 94:Suppl. 386

(134-136). Date of Publication: 1982 No outcomes of interest

26545794

Oumama El Ezzi and Georges Herzog and Martin Broome and Chantal Trichet-Zbinden and Judith Hohlfeld and Jacques Cherpillod and Anthony S de Buys Roessingh

Grommets and speech at three and six years in children born with total cleft or cleft palate

Dec No outcomes of interest

25598382 Wan X. and Yang J. and Jia H. Efficacy of surgery, recurrence factors and treatment strategies of otitis media with effusion in children

Zhonghua er bi yan hou tou jing wai ke za zhi = Chinese journal of otorhinolaryngology head and neck surgery (2014) 49:11 (964-967). Date of Publication: 1 Nov 2014

No primary data

B-10

PMID Author(s) Title Journal Exclusion Reason

8656164 A Adelman Water precautions in children with tympanostomy tubes The Journal of family practice No primary

data

15851429 M M Rovers and N Black and G G Browning and R Maw and G A Zielhuis and M P Haggard

Grommets in otitis media with effusion: an individual patient data meta-analysis Archives of disease in childhood No primary

data

6974210 L J Hall Chronic serous otitis media The Journal of the Kentucky Medical Association

No primary data

6357648 T Lildholdt

Secretory otitis media. The significance of negative middle ear pressure and the results of a controlled study of ventilation tubes

Danish medical bulletin No primary data

11509152 M B Stephens

Does delaying placement of tympanostomy tubes have an adverse effect on developmental outcomes in children with persistent middle ear effusions?

The Journal of family practice No primary data

1110316 L W Pratt The use of equalization tubes in nonsuppurative otits media The Journal of the Maine Medical Association No primary

data

8461735 A F Bisset Persistent glue ear in children BMJ (Clinical research ed.) No primary data

16299942 Early tymp tubes do not improve outcomes after 3+ years The Journal of family practice No primary

data

7017311 D E Gebhart Tympanostomy tubes in the otitis media prone child The Laryngoscope No primary

data

24438691

Chantal W B Boonacker and Maroeska M Rovers and George G Browning and Arno W Hoes and Anne G M Schilder and Martin J Burton

Adenoidectomy with or without grommets for children with otitis media: an individual patient data meta-analysis

Health technology assessment (Winchester, England)

No primary data

8404550 C Deguine and J L Pulec Long-term ventilation myringostomy Ear, nose, & throat journal No primary data

567665 M E Alberts Ventilation of glue ears Journal of the Iowa Medical Society No primary data

8482269 M D Poole Treatment of otorrhea associated with tubes or perforations Ear, nose, & throat journal No primary

data

24524194 Chin-Lung Kuo and Yuan-Heng Tsao and An-Suey Shiao

Critical reassessment of the probability of receiving additional ventilation tube insertion for recurrent otitis media with effusion in children with cleft palate

Acta oto-laryngologica No primary data

B-11

PMID Author(s) Title Journal Exclusion Reason

880099 D W Johnson and R H Mathog and R H Maisel

Tympanostomy tube protection with ear plugs

Archives of otolaryngology (Chicago, Ill. : 1960)

No primary data

3522165 The surgical management of glue ear Drug and therapeutics bulletin No primary data

3743473 I J Moore and G F Moore and A J Yonkers Otitis media in the cleft palate patient Ear, nose, & throat journal No primary

data

1009868 B K Devgan Spoon-bobbin drain tube Ear, nose, & throat journal No primary data

11115295 C Giannoni Swimming with tympanostomy tubes Archives of otolaryngology--head & neck surgery

No primary data

853006 R Reck A rare complication of use of the middle ear ventilation tube (PVC) HNO No primary

data

17537888 Morten Lindbaek

Prompt insertion of tympanostomy tubes in infants and toddlers with persistent middle ear effusion did not improve developmental outcomes at 9-11 years of age

Evidence-based medicine No primary data

4079654 V Cerkez [Treatment of secretory otitis: medical or surgical therapy?] Lijec̆nic̆ki vjesnik No primary

data

1416480 A Clarós [Otitis media. Surgical treatment] Anales españoles de pediatría No primary data

8494594 P Federspil [Treatment of "suppurating ear" with intact middle ear tubes] Laryngo- rhino- otologie No primary

data

6778337 J L Paradise and C D Bluestone and K D Rogers and F H Taylor

Efficacy of adenoidectomy in recurrent otitis media. Historical overview and preliminary results from a randomized, controlled trial

The Annals of otology, rhinology & laryngology. Supplement

No primary data

12107957 Jørgen Lous and Maj-Britt Glenn Lauritsen

[Inserted tympanostomy tube in prolonged secretory otitis has no effect on language development]

Ugeskrift for laeger No primary data

1161091 R J van der Wal [Swimming with perforated tympanic membrane?] Nederlands tijdschrift voor geneeskunde No primary

data

6576790 N Fernández-Blasini [Tonsils, adenoids and related problems: use and abuse of ventilation tubes]

Boletín de la Asociación Médica de Puerto Rico

No primary data

1535965 C Chavanne [Surgical treatment of secretory otitis media in children] Revue médicale de la Suisse romande No primary

data

Poole M.D. Bacterial resistance to quinolone otic drops is nearly zero

Ear, Nose and Throat Journal (2007) 86:11 SUPPL. 1 (13-14). Date of Publication: November 2007

No primary data

4819101 Mawson S.R. Middle ear effusions: therapy and clinical Annals of Otology, Rhinology and No primary

B-12

PMID Author(s) Title Journal Exclusion Reason

results Laryngology (1974) 83:11 sup (71-72). Date of Publication: 1974

data

Brown M.W. Glue ear South Australian Clinics (1975) 7:1 (69-71). Date of Publication: 1975

No primary data

Husson Y. and Troy C. Tubal catarrh Concours Medical (1975) 97:33 (5041-5048). Date of Publication: 1975

No primary data

11115297 Brodsky L. Swimming with tympanostomy tubes: The controversy continues

Archives of Otolaryngology - Head and Neck Surgery (2000) 126:12 ([d]1509). Date of Publication: 2000

No primary data

6077690 Deutsch H.J.

Serous otitis media. An effective, practical approach to diagnosis and therapy of this most common cause of conductive loss of hearing in children

Penn. Med. (1967) 70:11 (53-55). Date of Publication: 1967

No primary data

5773899 Cross J.P. The expanding role of tympanostomy tubes Virginia Med.Mth. (1969) 96:2 (387-393). Date of Publication: 1969

No primary data

1549417 Landay S.E. and Schwartz R.H. Recommendations for swimming for children with ear infection and/or associated complications

Pediatric Infectious Disease Journal (1992) 11:1 (58-59). Date of Publication: 1992

No primary data

Mees K. The use of grommets in serous otitis media Munchener Medizinische Wochenschrift (1982) 124:11 (39-44). Date of Publication: 1982

No primary data

Namyslowski G. and Gierek T. and Pilch J. and Iwanowski P. Tarflen tubes for draining of tympanic cavity Otolaryngologia Polska (1987) 41:5 ( 334-

338). Date of Publication: 1987 No primary data

Dohar J.E. Are topical quinolones safe for middle ear use in children?

Ear, Nose and Throat Journal (2006) 85:10 SUPPL. 1 (6-7). Date of Publication: October 2006

No primary data

Rovers M.M. and Krabbe P.F. and Straatman H.

Ventilation tubes did not improve quality of life in persistent otitis media with effusion

Evidence-Based Medicine (2001) 6:4 (121). Date of Publication: 2001

No primary data

8486102 Pulec J.L. and Deguine C. Secretory otitis media (Glue Ear) Ear, Nose and Throat Journal (1993) 72:4 (254). Date of Publication: 1993

No primary data

25695362 Chin-Lung Kuo A critical appraisal of ventilation tube insertion in children with cleft palate Feb No primary

data

25677370 Joong Ho Ahn and Woo Seok Kang and Ji Heui Kim and Kyung S Koh and Tae Hyun Yoon

Critical reassessment of the probability of receiving additional ventilation tube insertion for recurrent otitis media with effusion in children with a cleft palate

May No primary data

24524194 Chin-Lung Kuo and Yuan-Heng Tsao and An-Suey Shiao

Critical reassessment of the probability of receiving additional ventilation tube May No primary

data

B-13

PMID Author(s) Title Journal Exclusion Reason

insertion for recurrent otitis media with effusion in children with cleft palate

Outhoff, K. Grommets No primary data

26216610 Del Mar, C. D. and Hoffmann, T. Autoinflation: An effective nondrug intervention for glue ear No primary

data

Anonymous

Erratum to: Long term complications of ventilation tube insertion in children with otitis media with effusion: Vojnosanit Pregl 2015; 72(1): 40-43

No primary data

1102070 Alejandro Hoberman Efficacy of Tympanostomy Tubes for Children With Recurrent Acute Otitis Media No primary

data

16480003

Takeshi Yagi and Ken Hayashi and Hisayoshi Shikii and Yuko Miyamoto and Makoto Oda and Atsushi Shinkawa

[Effect of volume reduction surgery by radiofrequency for enlarged adenoid causing recurrent otitis media with effusion]

Nihon Jibiinkoka Gakkai kaiho Not intervention of interest

25215630 Kavita Dedhia and Sukgi Choi and David H Chi

Management of refractory tympanostomy tube otorrhea with ear wicks Mar Not intervention

of interest

25873182

Mirjana Kostić and Ksenija Ribarić Jankes and Robert Trotić and Mihael Ries and Branka Ledić and Vladimir Bedeković

Clinical and audiological findings in children with acute otitis media Jul Not intervention

of interest

26281252

Wenrong Jiang and Tao He and Qian Zheng and Wei Zheng and Bing Shi and Chao Yang and Chenghao Li

[Integrated assessment of middle ear dysfunction in cleft palate patients and optimization of therapeutic schedule]

Hua xi kou qiang yi xue za zhi = Huaxi kouqiang yixue zazhi = West China journal of stomatology

Not intervention of interest

6540371 S J de Vries and R Wentges [Ear drum grommets and swimming] Nederlands tijdschrift voor geneeskunde Not intervention of interest

10406313 O C Ilicali and N Keleş and K Değer and I Savaş

Relationship of passive cigarette smoking to otitis media

Archives of otolaryngology--head & neck surgery

Not intervention of interest

9253394 S M Marcus Assessing non-consent bias with parallel randomized and nonrandomized clinical trials

Journal of clinical epidemiology Not intervention of interest

25873182

Mirjana Kostić and Ksenija Ribarić Jankes and Robert Trotić and Mihael Ries and Branka Ledić and Vladimir Bedeković

Clinical and audiological findings in children with acute otitis media Acta oto-laryngologica Not intervention

of interest

3701198 E Vartiainen and J Kärjä and S Surgery of chronic otitis media in young The Journal of laryngology and otology Not intervention

B-14

PMID Author(s) Title Journal Exclusion Reason

Karjalainen patients of interest

962698 M C Gydé When the weeping stopped: an otologist views otorrhea and gentamicin

Archives of otolaryngology (Chicago, Ill. : 1960)

Not intervention of interest

14551787 Elbieta Hassmann and Boena Skotnicka and Maria Baczek and Małgorzata Piszcz

Laser myringotomy in otitis media with effusion: long-term follow-up

European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery

Not intervention of interest

25274185 A Qureishi and G Garas and A Mallick and D Parker

The psychosocial impact of hearing aids in children with otitis media with effusion The Journal of laryngology and otology Not intervention

of interest

21362577

Chang Ho Lee and Chan Kee Yoo and Jong Eui Hong and Hong Joong Kim and Dae Geun Lim and Kwang Joong Kim

Resolved effusion on myringotomy: a study of dry tap without general anesthesia

International journal of pediatric otorhinolaryngology

Not intervention of interest

20058316 Katrina Spilsbury and Ian Miller and James B Semmens and Francis J Lannigan

Factors associated with developing cholesteatoma: a study of 45,980 children with middle ear disease

The Laryngoscope Not population of interest

19091429 Yun Shan Phua and Lesley J Salkeld and Tristan M B de Chalain

Middle ear disease in children with cleft palate: protocols for management

International journal of pediatric otorhinolaryngology

Not population of interest

4470582 I S Thomson Exudative otitis media, grommets and cholesteatoma The Journal of laryngology and otology Not population

of interest

7098686 H Heumann and E Steinbach and R Seuffer

[A clinical and experimental study on precious metal ventilation tubes (author's transl)]

Laryngologie, Rhinologie, Otologie Not population of interest

Fujita A. and Kurata K. and Takahashi H. and Takagita S.

Clinical efficacy of clarithromycin treatment of refractory otitis media with effusion

Practica Otologica (1994) 87:9 (1287-1291). Date of Publication: 1994

Not population of interest

7642987 H L Tay and R P Mills Tympanic membrane atelectasis in childhood otitis media with effusion The Journal of laryngology and otology Not population

of interest

6380828 C H Bulman and S J Brook and M G Berry

A prospective randomized trial of adenoidectomy vs grommet insertion in the treatment of glue ear

Clinical otolaryngology and allied sciences Per ear assignment

6598263 T Lildholdt Consequences of ventilation tube treatment Acta oto-laryngologica. Supplementum Per ear assignment

2037414 M J Cunningham and E H Harley Preventing perioperative obstruction of tympanostomy tubes: a prospective trial of a simple method

International journal of pediatric otorhinolaryngology

Per ear assignment

5070299 D Kilby and S H Richards and G Hart Grommets and glue ears: two-year results The Journal of laryngology and otology Per ear

assignment

B-15

PMID Author(s) Title Journal Exclusion Reason

3389234 A R Maw Tonsils and adenoids. Their relation to secretory otitis media Advances in oto-rhino-laryngology Per ear

assignment

9199524 M Gaihede and T Lildholdt and J Lunding

Sequelae of secretory otitis media: changes in middle ear biomechanics Acta oto-laryngologica Per ear

assignment

2394020 A J Parker and A R Maw and J E Powell

Intra-tympanic membrane bleeding after grommet insertion and tympanosclerosis Clinical otolaryngology and allied sciences Per ear

assignment

3524910 N Black and J Crowther and A Freeland

The effectiveness of adenoidectomy in the treatment of glue ear: a randomized controlled trial

Clinical otolaryngology and allied sciences Per ear assignment

21072756 Paul Hong and Neil Smith and Liane B Johnson and Gerard Corsten

A randomized double-blind controlled trial of phosphorylcholine-coated tympanostomy tube versus standard tympanostomy tube in children with recurrent acute and chronic otitis media

The Laryngoscope Per ear assignment

2872514 A R Maw and F Herod

Otoscopic, impedance, and audiometric findings in glue ear treated by adenoidectomy and tonsillectomy. A prospective randomised study

Lancet (London, England) Per ear assignment

2196954 N A Black and C F Sanderson and A P Freeland and M P Vessey

A randomised controlled trial of surgery for glue ear BMJ (Clinical research ed.) Per ear

assignment

1919311 A R Maw Development of tympanosclerosis in children with otitis media with effusion and ventilation tubes

The Journal of laryngology and otology Per ear assignment

650647 M J Brown and S H Richards and A G Ambegaokar

Grommets and glue ear: a five-year follow up of a controlled trial Journal of the Royal Society of Medicine Per ear

assignment

3348665 H R Grant and R E Quiney and D M Mercer and S Lodge Cleft palate and glue ear Archives of disease in childhood Per ear

assignment

3243009 D W Skinner and T H Lesser and S H Richards

A 15 year follow-up of a controlled trial of the use of grommets in glue ear Clinical otolaryngology and allied sciences Per ear

assignment

16368152 Uneri C. and Baglam T. and Yazici M.

The effect of Vitamin E treatment on the development of myringosclerosis after ventilation tube insertion

International Journal of Pediatric Otorhinolaryngology (2006) 70:6 (1045-1048). Date of Publication: June 2006

Per ear assignment

10912691 Banerjee A.R. and Jennings C. and Marshall J.N. and Narula A.A.

The effect of topical adrenaline on the development of myringosclerosis after tympanostomy tube insertion

American Journal of Otology (2000) 21:4 (482-484). Date of Publication: July 2000

Per ear assignment

4925501 Richards S.H. Grommets and glue ears: A clinical trial J.Laryng (1971) 85:1 (155-156). Date of Publication: 1971

Per ear assignment

Coates H. and Chai F. and Oates The use of surface treated and silver oxide Australian Journal of Otolaryngology (1998) Per ear

B-16

PMID Author(s) Title Journal Exclusion Reason

J. impregnated tympanostomy tubes in reducing post-operative otorrhoea

3:1 (16-19). Date of Publication: Jan 1998 assignment

27063749 Han Zhang and Yaser Alrajhi and Hamdy El-Hakim

Variables associated with repeated ventilation tube insertion in healthy non-syndromic children

May Retrospective cohort N < 1000

456299 M Kremer and L Podoshin and M Fradis

Treatment of serous otitis media with tympanic ventilation tubes Ear, nose, & throat journal

Retrospective cohort N < 1000

16214225 Ingrid Augustsson and Ingemar Engstrand

Hearing loss as a sequel of secretory and acute otitis media as reflected by audiometric screening of Swedish conscripts

International journal of pediatric otorhinolaryngology

Retrospective cohort N < 1000

2845850 M François and O Laccourreye and J N Margo and V Herman and P Narcy

[Short-term complications of transtympanic aerators]

Annales d'oto-laryngologie et de chirurgie cervico faciale : bulletin de la Société d'oto-laryngologie des hôpitaux de Paris

Retrospective cohort N < 1000

8470547 E Manders and J Tyberghein The effects of ventilation tube placement on hearing, speech, language, cognition and behaviour

Acta oto-rhino-laryngologica Belgica Retrospective cohort N < 1000

Walker P. Persistent perforation following spontaneous extrusion of ventilation tubes in children

Australian Journal of Otolaryngology (2003) 6:1 (18-23). Date of Publication: May 2003

Retrospective cohort N < 1000

Somekawa Y. Ear discharge following insertion of tympanostomy tube

Oto-Rhino-Laryngology Tokyo (1981) 24:6 (23-31+3). Date of Publication: 1981

Retrospective cohort N < 1000

26443477 Richard M Rosenfeld and Krishna Sury and Christopher Mascarinas

Office Insertion of Tympanostomy Tubes without Anesthesia in Young Children Dec

Retrospective cohort N < 1000

12567079 Ron B Mitchell and Ellen Call and James Kelly

Ear, nose and throat disorders in children with Down syndrome The Laryngoscope

Retrospective cohort N < 1000

1451676 S S Hussain Extrusion rate of Shah and Shepard ventilation tubes in children Ear, nose, & throat journal

Retrospective cohort N < 1000

16822553 Fatma Homood Al Anazy Iatrogenic cholesteatoma in children with OME in a training program

International journal of pediatric otorhinolaryngology

Retrospective cohort N < 1000

12707661 M Tayyar Kalcioglu and Yasar Cokkeser and Ahmet Kizilay and Orhan Ozturan

Follow-up of 366 ears after tympanostomy tube insertion: why is it draining?

Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery

Retrospective cohort N < 1000

B-17

PMID Author(s) Title Journal Exclusion Reason

17970145 Svetlana Diacova and Thomas J McDonald

A comparison of outcomes following tympanostomy tube placement or conservative measures for management of otitis media with effusion

Ear, nose, & throat journal Retrospective cohort N < 1000

15373873 D S Kim and P L A Moore and T J Rockley

Long-term Paparella II grommet use in the management of persistent childhood otitis media: a 5-year follow-up study

Clinical otolaryngology and allied sciences Retrospective cohort N < 1000

6890608 W M Luxford and J L Sheehy Myringotomy and ventilation tubes: a report of 1,568 ears The Laryngoscope

Retrospective cohort N < 1000

22518157 Bilal Gani and A J Kinshuck and R Sharma

A review of hearing loss in cleft palate patients International journal of otolaryngology

Retrospective cohort N < 1000

7242199 J H Per-Lee Long-term middle ear ventilation The Laryngoscope Retrospective cohort N < 1000

8436454 K S Mangat and G A Morrison and T M Ganniwalla

T-tubes: a retrospective review of 1274 insertions over a 4-year period

International journal of pediatric otorhinolaryngology

Retrospective cohort N < 1000

6874239 J F Sederberg-Olsen and A E Sederberg-Olsen and A M Jensen

The prognostic significance of the air volume in the middle ear for the tendency to recurrence of secretory middle ear condition

International journal of pediatric otorhinolaryngology

Retrospective cohort N < 1000

3835916

Y Kawasaki and Y Sakamoto and Y Honmura and T Tatehara and K Miyagawa and Y Urao and J Kanzaki

Long-term results of ventilation tube for otitis media with effusion in children Auris, nasus, larynx

Retrospective cohort N < 1000

9118577 D Strachan and G Hope and M Hussain

Long-term follow-up of children inserted with T-tubes as a primary procedure for otitis media with effusion

Clinical otolaryngology and allied sciences Retrospective cohort N < 1000

4809194 Paradise J.L. and Bluestone C.D. Early treatment of the universal otitis media of infants with cleft palate

Pediatrics (1974) 53:1 (48-54). Date of Publication: 1974

Retrospective cohort N < 1000

Laurikainen E. and Suonpaa J. Topical use of aminoglycoside ear drops in children with purulent draining ventilation tubes. A follow-up study

Acta Oto-Laryngologica (1984) 98:SUPPL. 412 (103-104). Date of Publication: 1984

Retrospective cohort N < 1000

Kowata I. and Kobayashi S. and Onodera A.

Follow-up study of secretory otitis media in children

Otologia Fukuoka (1979) 25:SUPPL. 1 (153-157). Date of Publication: 1979

Retrospective cohort N < 1000

B-18

PMID Author(s) Title Journal Exclusion Reason

Ichihara T. and Haginomori S.-I. and Mori A. and Kanazawa A. and Nishikado A. and Kawata R.

Ventilation tube treatment in children with otitis media with effusion

Otolaryngology - Head and Neck Surgery (United States) (2012) 147 SUPPL. 2 (P225). Date of Publication: August 2012

Retrospective cohort N < 1000

Boedts D. Middle ear ventilation and tympanic membrane tube (Dutch)

Tijdschrift voor Geneeskunde (1975) 31:8 (395-397). Date of Publication: 1975

Retrospective cohort N < 1000

Gristwood R. Management of the draining ventilation tube in secretory otitis media

Australian Journal of Otolaryngology (1998) 3:2 (147-148). Date of Publication: 1998

Retrospective cohort N < 1000

Meghji S. and Rea P. Follow-up audit for grommets for persistent otitis media with effusion: Are we follow nice guidelines?

International Journal of Surgery (2013) 11:8 (637). Date of Publication: 2013

Retrospective cohort N < 1000

3955712 F Odehnal and A Tomecková [Tympanic ventilation tubes in the so-called "glue ear"] Ceskoslovenská otolaryngologie

Retrospective cohort N < 1000

4040160 Y Somekawa and K Kobayashi and T Yamaguchi and K Shimoda and T Suzuki and A Kataura

[Long-term result of grommets in children with secretory otitis media] Nihon Jibiinkoka Gakkai kaiho

Retrospective cohort N < 1000

12235880 Hiroshi Ogawa [Otitis media with effusion: a study of 346 cases in an outpatient clinic] Nihon Jibiinkoka Gakkai kaiho

Retrospective cohort N < 1000

2594453 M E Pichichero and L R Berghash and A S Hengerer

Anatomic and audiologic sequelae after tympanostomy tube insertion or prolonged antibiotic therapy for otitis media

The Pediatric infectious disease journal Retrospective cohort N < 1000

3927225 M R Klingensmith and M Strauss and G H Conner

A comparison of retention and complication rates of large-bore (Paparella II) and small-bore middle ear ventilating tubes

Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery

Retrospective cohort N < 1000

16813031 Stanley Mui and Barry M Rasgon and Raymond L Hilsinger and Brent Lewis and Gretchen Lactao

Tympanostomy tubes for otitis media: quality-of-life improvement for children and parents

Ear, nose, & throat journal Retrospective cohort N < 1000

5058477 S R Mawson and P Fagan Tympanic effusions in children. Long-term results of treatment by myringotomy, aspiration and indwelling tubes (grommets)

The Journal of laryngology and otology Retrospective cohort N < 1000

4041175 V Svane-Knudsen and T Lildholdt Sequelae of ventilation tubes following tonsillectomy Archives of oto-rhino-laryngology

Retrospective cohort N < 1000

2037413 B H Matt and R P Miller and R M Meyers and J M Campbell and R T Cotton

Incidence of perforation with Goode T-tube International journal of pediatric otorhinolaryngology

Retrospective cohort N < 1000

B-19

PMID Author(s) Title Journal Exclusion Reason

3698323 J W Curley Grommet insertion: some basic questions answered Clinical otolaryngology and allied sciences

Retrospective cohort N < 1000

955999 A E Kortekangas and E Virolainen [Experiences with polyethylene ventilation tubes in children with recurrent middle ear inflammation (author's transl)]

HNO Retrospective cohort N < 1000

2631910 M T Dueñas Polo and J L Pardal Refoyo and A Ramos Macías and F Ruiz Martín and A Cañizo Alvarez

[Transtympanic ventilation tubes and serous otitis media. Study of 100 cases] Acta otorrinolaringológica española

Retrospective cohort N < 1000

1867910 J Vallés Fontanet and X Perramón Montoliu

[The clinical evolution of transtympanic ventilation tubes in serous otitis. A study of 123 cases]

Acta otorrinolaringológica española Retrospective cohort N < 1000

6538920 G Geyer [The seromucous tympanum] Laryngologie, Rhinologie, Otologie Retrospective cohort N < 1000

7873230

J A Jiménez Antolín and O Lasso Luis and E Muñoz Platón and M Rodríguez Francos and E Galdeano Granda

[Myringotomy and transtympanic ventilation tubes in secretory otitis media. A study of 108 children]

Acta otorrinolaringológica española Retrospective cohort N < 1000

15583925 V Gudziol and W J Mann [Otological findings in adults with isolated cleft palate or cleft lip, jaw, and palate] Mund-, Kiefer- und Gesichtschirurgie : MKG

Retrospective cohort N < 1000

3618986 P Canals Ruiz and J L Peris Beaufills and F López Catalá and C Morera Pérez

[Secretory otitis media: surgical treatment and results]

Anales otorrinolaringológicos ibero-americanos

Retrospective cohort N < 1000

8991399 J L Lacosta and M Zabaleta and I Erdozain

[The evolution of otitis media with effusion treated by transtympanic drainage] Acta otorrinolaringológica española

Retrospective cohort N < 1000

8928639 C Stenström and L Ingvarsson Late effects on ear disease in otitis-prone children: a long-term follow-up study Acta oto-laryngologica

Retrospective cohort N < 1000

26443477 Richard M Rosenfeld and Krishna Sury and Christopher Mascarinas

Office Insertion of Tympanostomy Tubes without Anesthesia in Young Children

Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery

Retrospective cohort N < 1000

5074564 N Stangeland [Otosalpingitis--treatment with a polyethylene tube in the ear drum]

Tidsskrift for den Norske lægeforening : tidsskrift for praktisk medicin, ny række

Retrospective cohort N < 1000

7462026 J E Hug and C R Pfaltz [Short- or long-term middle ear ventilation? (author's transl)] HNO Retrospective

cohort N <

B-20

PMID Author(s) Title Journal Exclusion Reason

1000

4636406 C von Sydow [Middle-ear drainage in otosalpingitis] Läkartidningen Retrospective cohort N < 1000

10853347 M Fücsek and M Gábriel [Long-term results of tube insertion in treating otitis media with effusion] Orvosi hetilap

Retrospective cohort N < 1000

3604104 K Haralampiev and B Kitanoski and B Ristić and M Jaćimović

[Surgical treatment of chronic secretory otitis using aeration-drainage tubes] Vojnosanitetski pregled

Retrospective cohort N < 1000

7569388 J P Dachy and I Evrard Revue de laryngologie - otologie - rhinologie Retrospective cohort N < 1000

8191069 F Devars and L Traissac [Goode's transtympanic drains. Indications and complications] Revue de laryngologie - otologie - rhinologie

Retrospective cohort N < 1000

16903334 Beata Zielnik-Jurkiewicz and Olga Olszewska-Sosińska and Magdalena Rakowska

[Results of treatment with tympanostomy tubes in children with otitis media with effusion]

Otolaryngologia polska = The Polish otolaryngology

Retrospective cohort N < 1000

9518333 B Zielnik-Jurkiewicz and J Gutkowska

[Effect of surgical treatment of otitis media with effusion on children. Personal experience]

Otolaryngologia polska = The Polish otolaryngology

Retrospective cohort N < 1000

156771 M Wayoff and J P Kocher and C Chobaut and C Simon

[Long-term results of transtympanic drainage]

Journal français d'oto-rhino-laryngologie; audiophonologie, chirurgie maxillo-faciale

Retrospective cohort N < 1000

4039907 M Klein [Presentation and trial of a new medium-duration transtympanic ventilator]

Annales d'oto-laryngologie et de chirurgie cervico faciale : bulletin de la Société d'oto-laryngologie des hôpitaux de Paris

Retrospective cohort N < 1000

3705232 J F Sederberg-Olsen and A E Sederberg-Olsen and A M Jensen

[Complications of grommets in specialist practice] Ugeskrift for laeger

Retrospective cohort N < 1000

10337163 S Chodynicki and B Lazarczyk [The results of treatment of otitis media with suppuration in children by ventilation tubes]

Otolaryngologia polska = The Polish otolaryngology

Retrospective cohort N < 1000

25554572 Axel Håkansson and Rut Florentzson and Lisa Tuomi and Caterina Finizia

Transmyringeal ventilation tube treatment in children: hearing outcome after 10 years

International journal of pediatric otorhinolaryngology

Retrospective cohort N < 1000

21846926 Inessa Fishman and Kevin J Sykes Demographics and microbiology of Otolaryngology--head and neck surgery : Retrospective

B-21

PMID Author(s) Title Journal Exclusion Reason

and Rebecca Horvat and Rangaraj Selvarangan and Jason Newland and Julie L Wei

otorrhea through patent tubes failing ototopical and/or oral antibiotic therapy

official journal of American Academy of Otolaryngology-Head and Neck Surgery

cohort N < 1000

9119591

T Saito and E Iwaki and Y Kohno and T Ohtsubo and I Noda and S Mori and T Yamamoto and Y Shibamori and H Saito

Prevention of persistent ear drum perforation after long-term ventilation tube treatment for otitis media with effusion in children

International journal of pediatric otorhinolaryngology

Retrospective cohort N < 1000

16500457 Frank Hill The Triune, a new silicone tympanostomy tube

Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery

Retrospective cohort N < 1000

16230588 James M Coticchia and Joseph E Dohar

Methicillin-resistant Staphylococcus aureus otorrhea after tympanostomy tube placement

Archives of otolaryngology--head & neck surgery

Retrospective cohort N < 1000

3835921 N Yanagihara and T Yagi Limitation of long term ventilation tube: in view of complications and hearing restoration

Auris, nasus, larynx Retrospective cohort N < 1000

26115935 Mallory B O'Niel and Laura D Cassidy and T Roxanne Link and Joseph E Kerschner

Tracking tympanostomy tube outcomes in pediatric patients with otitis media using an electronic database

International journal of pediatric otorhinolaryngology

Retrospective cohort N < 1000

3835931 M Sakai and A Shinkawa and S Saito and H Miyake

Late results of hearing in children treated with tympanostomy tube Auris, nasus, larynx

Retrospective cohort N < 1000

4843116 L A Hughes and F R Warder and W R Hudson Complications of tympanostomy tubes Archives of otolaryngology (Chicago, Ill. :

1960)

Retrospective cohort N < 1000

11564294 Y Talmon and H Gadban and A Samet and P Gilbey and V Letichevsky

Medium-term middle ear ventilation with self-manufactured polyethylene T-tubes for the treatment of children with middle ear effusion

The Journal of laryngology and otology Retrospective cohort N < 1000

9853658

E Iwaki and T Saito and G Tsuda and C Sugimoto and Y Kimura and N Takahashi and K Fujita and H Sunaga and H Saito

Timing for removal of tympanic ventilation tube in children Auris, nasus, larynx

Retrospective cohort N < 1000

6685748 M Ben-Ami and G Rosen and T Shlezinger and S Konack and M Ben-Ami

Otitis media with effusion--complications after treatment The Journal of laryngology and otology

Retrospective cohort N < 1000

6778333 W Draf and P Schulz Insertion of ventilation tubes into the medical ear: results and complications. A seven-year review

The Annals of otology, rhinology & laryngology. Supplement

Retrospective cohort N < 1000

B-22

PMID Author(s) Title Journal Exclusion Reason

7192378 J J Holt and S G Harner Effects of large-bore middle ear ventilation tubes Otolaryngology and head and neck surgery

Retrospective cohort N < 1000

11738691 Oren Friedman and Ellen S Deutsch and James S Reilly and Steven P Cook

The feasibility of office-based laser-assisted tympanic membrane fenestration with tympanostomy tube insertion: the duPont Hospital experience

International journal of pediatric otorhinolaryngology

Retrospective cohort N < 1000

8588632 A G Schilder and G A Zielhuis and M P Haggard and P van den Broek

Long-term effects of otitis media with effusion: otomicroscopic findings The American journal of otology

Retrospective cohort N < 1000

3915206 T J Balkany and I K Arenberg and R L Steenerson

Middle ear irrigation during insertion of ventilation tubes Auris, nasus, larynx

Retrospective cohort N < 1000

15829063 Marie Ryding and Peter White and Olof Kalm

Course and long-term outcome of 'refractory' secretory otitis media The Journal of laryngology and otology

Retrospective cohort N < 1000

12472518 P Sheahan and A W Blayney and J N Sheahan and M J Earley

Sequelae of otitis media with effusion among children with cleft lip and/or cleft palate

Clinical otolaryngology and allied sciences Retrospective cohort N < 1000

26043589

Vladimir Djordjević and Bojana Bukurov and Nenad Arsović and Snežana Ješić and Jovica Milovanović and Vladimir Nešić

Long term complications of ventilation tube insertion in children with otitis media with effusion

Vojnosanitetski pregled Retrospective cohort N < 1000

3835919 M Suzuki and K Kodera

Long term follow-up of secretory otitis media in children: the effects of adenotonsillectomy with insertion of a ventilation tube

Auris, nasus, larynx Retrospective cohort N < 1000

3189124 L A Hughes and D Wight Tympanostomy tubes: long-term effects American family physician Retrospective cohort N < 1000

969088 D G Pappas Triflanged tube for chronic serous otitis media

Transactions. Section on Otolaryngology. American Academy of Ophthalmology and Otolaryngology

Retrospective cohort N < 1000

18225626 Arthur H Allen Is i.v. access necessary for myringotomy with tubes? Ear, nose, & throat journal

Retrospective cohort N < 1000

3427799 R W Slack and J M Gardner and C Chatfield

Otorrhoea in children with middle ear ventilation tubes: a comparison of different types of tubes

Clinical otolaryngology and allied sciences Retrospective cohort N < 1000

B-23

PMID Author(s) Title Journal Exclusion Reason

6085804

P Arcand and P Gauthier and G Bilodeau and G Chapados and A Abela and R Desjardins and P P Gagnon and A J Guerguerian

Post-myringotomy care: a prospective study The Journal of otolaryngology

Retrospective cohort N < 1000

1011326 T Palva and E Kokko Middle ear effusions -- complications of disease and treatment The Journal of otolaryngology

Retrospective cohort N < 1000

10994430 G D Smyth and C C Patterson and S Hall

Tympanostomy tubes: do they significantly benefit the patient?

Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery

Retrospective cohort N < 1000

2589073 J F Sederberg-Olsen and A E Sederberg-Olsen and A M Jensen

Late results of treatment with ventilation tubes for secretory otitis media in ENT practice

Acta oto-laryngologica Retrospective cohort N < 1000

24735607 Hye Ran Hong and Tae Su Kim and Jong Woo Chung

Long-term follow-up of otitis media with effusion in children: comparisons between a ventilation tube group and a non-ventilation tube group

International journal of pediatric otorhinolaryngology

Retrospective cohort N < 1000

6682411 G Pestalozza and G Cusmano and E Tessitore and A Bonelli

Transtympanic drains in the treatment of serous otitis in children; anatomical versus functional long term results

International journal of pediatric otorhinolaryngology

Retrospective cohort N < 1000

20359098 Qi Gui and Zhinan Wang and Ping Chen

[Retaining time of tympanic ventilation tube and aural complications]

Lin chuang er bi yan hou tou jing wai ke za zhi = Journal of clinical otorhinolaryngology, head, and neck surgery

Retrospective cohort N < 1000

23002647 Ningbo Wang and Enqin Zhang and Chunbo Lan and Wenwen Xiao and Jiabin Liu

[Clinical research of T tube implantation on children with chronic otitis media]

Lin chuang er bi yan hou tou jing wai ke za zhi = Journal of clinical otorhinolaryngology, head, and neck surgery

Retrospective cohort N < 1000

1874637 J Mertens and B Schwenk [Cholesteatoma and chronic tubal middle ear infection in children. A 10 year overview]

HNO Retrospective cohort N < 1000

26281253

Sen Li and Hong Zhang and Yun Wei and Xilei Zhang and Yingru Wu and Jiang Qian and Liang Shen and Zhengjian Zhang

[Clinical comparative study on the treatment characteristics of secretory otitis media between cleft and non-cleft palate patients]

Jun Retrospective cohort N < 1000

9055175 Hui Y. and Park A. and Crysdale W.S. and Forte V. Ototoxicity from ototopical aminoglycosides Journal of Otolaryngology (1997) 26:1 (53-

56). Date of Publication: February 1997

Retrospective cohort N < 1000

6821430 Leopold D.A. and McCabe B.F. Factors influencing tympanostomy tube function and extrusion: A study of 1,127 ears

Otolaryngology - Head and Neck Surgery (1980) 88:4 (447-454). Date of Publication: 1980

Retrospective cohort N < 1000

B-24

PMID Author(s) Title Journal Exclusion Reason

26548470 Gabriella Fekete-Szabó and Fekete Kiss and László Rovó

[Long-term follow-up after tympanostomy tube insertion in children with serous otitis media]

Nov Retrospective cohort N < 1000

27067029

Chii-Yuan Huang and Chuan-Song Wu and Chao-Hsiun Tang and Mao-Che Wang and Ting-Yu Kuo and Tzong-Yang Tu

Palatoplasty decreases the re-insertion rate of middle ear ventilation tube in cleft palate children - A population-based birth cohort study

Apr Retrospective cohort N < 1000

6542693 M Lucić [Therapy of exudative chronic otitis using ventilating tubes. Results and consequences]

Srpski arhiv za celokupno lekarstvo Reviewed in abstract only

10377838 S Sanković and R Dergenc [Surgical treatment of secretory otitis media: persistent perforation as a rare complication]

Srpski arhiv za celokupno lekarstvo Reviewed in abstract only

22433702 [First experience with the use of tympanostomy for the management of acute otitis media in children]

Vestnik otorinolaringologii Reviewed in abstract only

21166142

Elzbieta Hassmann-Poznańska and Artur Goździewski and Małgorzata Piszcz and Hanna Zajaczkiewicz and Bozena Skotnicka

[Influence of tympanic membrane changes on immittance and extended frequency audiometric findings]

Otolaryngologia polska = The Polish otolaryngology

Reviewed in abstract only

7725152 B Ristić and K Haralampiev and R Filipovski

[Complications in secretory otitis media treated with aeration-drainage tubes] Srpski arhiv za celokupno lekarstvo Reviewed in

abstract only

Viada J. and Carcamo F. and Carrillo L.

Evaluation of results with middle ear ventilation tubes in treatment of serous otitis

Revista de Otorrinolaringologia y Cirurgia de Cabeza y Cuello (1979) 39:2 (47-55). Date of Publication: 1979

Reviewed in abstract only

Sanchez T.G. and Ognibene R.Z. and Gondin M. and Bento R.F.

Audiometric findings after ear ventilation tubes extrusion

Revista Brasileira de Otorrinolaringologia (1992) 58:2 (99-102). Date of Publication: 1992

Reviewed in abstract only

Scherer H. Transtympanic ventilation of the middle ear by means of tympanic drainage

Praxis Magazin Med. (1995) :3 (44+46). Date of Publication: 1995

Reviewed in abstract only

Suzuki M. A long-term follow-up of secretory otitis media in children

Otolaryngology (1984) 56:7 (469-473). Date of Publication: 1984

Reviewed in abstract only

Neubauer R. and Slama K.

Experience with the use of a ventilation tube STIPULA in the treatment of otitis media chronica secretoria at the ENT department of the masaryk hospital in Usti nad Labem during a 17-year period

Otorinolaryngologie a Foniatrie (2003) 52:2 (65-70). Date of Publication: 2003

Reviewed in abstract only

Ohnishi T. Comparative study of middle ear ventilating tubes

Otolaryngology (1980) 52:8 (575-581). Date of Publication: 1980

Reviewed in abstract only

B-25

PMID Author(s) Title Journal Exclusion Reason

Paquelin F. and Doncieux D. and Luboinski B. and Henin J.M.

Continuous transtympanic drainage in children with a non purulent cryptogenetic exudate of the middle ear

ANN.OTO-LARYNG. (1973) 90:9 (565-569). Date of Publication: 1973

Reviewed in abstract only

Yokoyama T. Results of tympanostomy tube for children with secretory otitis media

Otolaryngology (1979) 51:9 (655-660). Date of Publication: 1979

Reviewed in abstract only

Prauzinska M. and Sroczynski J. and Pucher B. and Szydlowski J.

The effectiveness of ventilation tubes treatment in otitis media with effusion in children

Family Medicine and Primary Care Review (2014) 16:3 (277-278). Date of Publication: July-September 2014

Reviewed in abstract only

Rashid D. and Ahmad B. and Malik S.M. and Rahat Z.M. and Malik K.Z.

Otitis media with effusion-cost effective options

Journal of the College of Physicians and Surgeons Pakistan (2002) 12:5 (274-276). Date of Publication: 2002

Reviewed in abstract only

Attallah M.S. and Essa A.E. Common complications following ventilation tube insertion

Indian Journal of Otology (1999) 5:1 (17-20). Date of Publication: 1999

Reviewed in abstract only

Yagi T. The long-term result of middle far ventilation tube

Otolaryngology (1985) 57:6 (463-468). Date of Publication: 1985

Reviewed in abstract only

Bartonkova K. and Janecek D. and Lenert R.

Mean time of insertion of a pressure equalizing tube (PET)

Otorinolaryngologie a Foniatrie (2002) 51:3 (161-164). Date of Publication: 2002

Reviewed in abstract only

Slapak I. and Hornik P. and Machac J. and Machalova M. and Fryckova A. and Chrobok V. and Vokurka J. and Hybasek I.

Use of a ventilation tube and recurrent otitis media in child age

Otorinolaryngologie a Foniatrie (1999) 48:3 (143-146). Date of Publication: 1999

Reviewed in abstract only

Hatanaka E. Results of treatment with large ventilating tubes and grommet tubes in children with middle ear effusion

Otolaryngology (1983) 55:11 (915-919). Date of Publication: 1983

Reviewed in abstract only

Pospiech L. and Rak J. and Jaworska M. and Klempous J.

Effects of surgical and pharmacological management of otitis media with effusion in children admitted to the Otolaryngology Department of the Medical University of Wroclaw

Przeglad Pediatryczny (2001) 31:3 (215-218). Date of Publication: 2001

Reviewed in abstract only

20873100 Elzbieta Hassmann-Poznańska and Artur Goździewski and Małgorzata Piszcz and Bozena Skotnicka

[Long term sequelae of otitis media with effusion during childhood]

Otolaryngologia polska = The Polish otolaryngology

Reviewed in abstract only

26860606 Yakup Yegin and Mustafa Çelik and Burak Olgun and Hasan Emre Koçak and Fatma Tülin Kayhan

Is ventilation tube insertion necessary in children with otitis media with effusion? Dec Reviewed in

abstract only

26752135

Kate J Fitzsimons and Lynn P Copley and Jan H {van der Meulen} and Channa Panagamuwa and Scott A Deacon

Grommet Surgery in Children With Orofacial Clefts in England Jan Reviewed in

abstract only

B-26

Appendix C. Study Design Table C1. Key Question 1 design

Study Study design

Funding source

Inclusion criteria Tympanography

Hearing test

Age range

(y)

Subgroups Number of assessments/followup

duration (weeks) Bernard 1991 1861917 Canada

RCT Government

middle ear effusion for greater than 3 months

yes yes 2.5-7 Down's syndrome, Cleft palate, Speech/Language disorder, documented immune insufficiency

5/78

Casselbrant 2009 19819563 1997-2005 U.S.

RCT Not reported

bilateral middle-ear effusion (MEE) for at least 3 months, unilateral for 6months or longer or unilateral for 3 months after extrusion of a tympanostomy tube

. 2-4 Down's syndrome, Cleft palate, Other craniofacial anomalies

nd/78

Chaudhuri 2006 23120310 India

RCT Not reported

. yes yes 0-12 2/8 weeks

Gates 1987 3683478 4/1980-6/1984 U.S.

RCT Government/Industry

Middle ear effusion without pain, redness, or bulging of the tympanic membrane

. yes 0-8 18/104

Mandel 1992 1565550 11/1981-06/1987 U.S.

RCT Government/Academic/Hospital

middle ear effusion lasted at least 2 months; middle ear effusion persisting after at least one 14-day abx and pseudoephedrine hydrochloride-maleate syrup; middle ear effusion persisting after at least one 14-day abx and pseudoephedrine hydrochloride-maleate syrup

. yes 0.58-12 excluded Down's syndrome, Other craniofacial anomalies, Pre-existing hearing loss, Speech/Language disorder, cystic fibrosis, DM, seizure, AOM, purulent rhinitis

36/156

Mandel 1989 2789777a 09/1979-

RCT Government

documented MEE of at least 2 months' duration; no symptoms consisting of otalgia or vertigo; MEE

. yes 0.58-12 excluded Down's syndrome, Other craniofacial anomalies, asthma, cystic fibrosis, diabetes mellitus, seizure

36/156

C-1

Study Study design

Funding source

Inclusion criteria Tympanography

Hearing test

Age range

(y)

Subgroups Number of assessments/followup

duration (weeks) 09/1984 U.S.

persisting after at least one 14-day course of an antimicrobial drug and pseudoephedrine hydrochloride-chlorpheniramine maleate syrup; no symptoms consisting of otalgia or vertigo; MEE persisting after at least one 14-day course of an antimicrobial drug and pseudoephedrine hydrochloride-chlorpheniramine maleate syrup

Mandel 1989 2789777b 09/1979-09/1984 U.S.

RCT Government

documented MEE of at least 2 months' duration; no symptoms consisting of otalgia or vertigo; MEE persisting after at least one 14-day course of an antimicrobial drug and pseudoephedrine hydrochloride-chlorpheniramine maleate syrup; no symptoms consisting of otalgia or vertigo; MEE persisting after at least one 14-day course of an antimicrobial drug and pseudoephedrine hydrochloride-chlorpheniramine maleate syrup

. yes 0.58-12 excluded Down's syndrome, Other craniofacial anomalies, asthma, cystic fibrosis, diabetes mellitus, seizure

36/156

Maw 1999 10459904, Hall-2009-19260880,

RCT Government

confirmation of bilateral OME by otoscopy; disruptions to speech, language, learning, or behaviour

yes yes DOB 4/1/1991-DOB 12/31/1

2/78

C-2

Study Study design

Funding source

Inclusion criteria Tympanography

Hearing test

Age range

(y)

Subgroups Number of assessments/followup

duration (weeks) Wilks-2000-10944051 4/1991-12/1992 UK

992

MRC Multicentre Otitis Media Study Group 2012 (TARGET) 22443163 15373863 12680834 4/1994-10/1998 UK

RCT Government

bilateral OME over 12-week watchful waiting period

yes yes 3.25-6.75

excluded History of ear or adenoid surgery

5/104

Nguyen 2004 15126745 01/1998-01/2003 Canada

RCT Not reported

OM with effusion persisting for more than 3 months or producing a conductive hearing loss (HL) greater than 30 dB with a type B tympanogram; or 3) both; more than three episodes during the preceding 6-month period or more than four during the preceding 12 month period; first surgical treatment of OM; first surgical treatment of OM

yes yes 1.5-18 excluded Down's syndrome, Other craniofacial anomalies, Primary ciliary dyskinesia, immune deficiency

>=2/52

Paradise 2001 11309632, 2005 16093466,

RCT Government/Industry

middle ear effusion that appeared substantial in quantity and persisted despite treatment with anti-microbial drugs for 90 days in the case

yes yes 0.04-1.17

nr/104

C-3

Study Study design

Funding source

Inclusion criteria Tympanography

Hearing test

Age range

(y)

Subgroups Number of assessments/followup

duration (weeks) 2003 12897272, 2007 17229952, Johnston2004 15231974 6/1991-12/1995 U.S.

of bilateral effusion or 135 days in the case of unilateral effusion.audiometric examinations; audiometric examinations

Popova 2010 20399511 2007-2009 Bulgaria

RCT No funding OME is defined as asymptomatic middle ear effusion without signs of inflammation characteristic of the acute otitis media (AOM).

yes yes 3-7 12/52 weeks

Rach 1991 2070526 Netherlands

RCT Government

bilateral flat tympanograms (type B) at two consecutive screenings at any time during the follow-up period

yes 2-2 excluded congenital ear disorders (sensonneural loss) or defects in their speech-producing apparatus (e.g. cleft palate), nehrological or serious visual disorders, emotional aberrations or mental defects

1/26

Rovers 2000 10969126, 2001 11124783, 2001 11409855, 2001 11470387, Ingels 2005 16429748, Hartman 2001

RCT Government

persistent (4–6 months) bilateral OME (confirmed by tympanometry and otoscopy) by the ENT surgeon during subsequent observations

yes yes 0-0.75 excluded Down's syndrome, Cleft palate, schisis, asthma, cystic fibrosis, and sensorineural hearing loss

3 successive tests; 3 monthly tympanometry and otoscopy measurements, audiometry every 6 months/52 weeks

C-4

Study Study design

Funding source

Inclusion criteria Tympanography

Hearing test

Age range

(y)

Subgroups Number of assessments/followup

duration (weeks) 11735817 01/1996-04/1997 Netherlands Velepic 2011 21397957 2004-2009 Croatia

RCT No funding CSOM lasting at least 3 months

. yes 2-12 >=6/>=26

Vlastos 2011 21205368 5/2007-5/2008 Greece

RCT Not reported

The diagnosis of OME was based on otoscopy, tympanography and pure tone audiometry. Specifically, the presence of an opaque or thickened tympanic membrane, air–fluid level, or bubbles, or the inability to visualise the incudostapedial joint, were considered signs of OME, in children with a type B tympanogram (compliance <0.2 ml) and an audiogram with an air–bone gap of 20 dB or a hearing loss of 30 dB but no more than 55 dB in at least one frequency in both ears. Absence of the light reflex was not regarded as a specific sign of OME.; Absence of the light reflex was not regarded as a specific sign of OME; Absence of the light reflex was not regarded as a specific sign of OME

yes yes 3-7 3/52 weeks

C-5

Study Study design

Funding source

Inclusion criteria Tympanography

Hearing test

Age range

(y)

Subgroups Number of assessments/followup

duration (weeks) De Beer 2004 15224825 1982-1983 Netherland

NRCS, prospective

Not reported

birth cohort of 1,439 subjects born in 1982 or 1983, chronic OME diagnosed as presence of ventilation tubes had been observed before the screening (0 to 24 months), during the screening at 2 to 4 years of age, in the period between both studies (4 to 8 years), and/or at the examination at 8 years, recurrent AOM diagnosed as parents had reported events of otalgia with fever and/or otorrhea during the screening at to 4 years of age, in the period between both studies (4 to 8 years), and/or at the examination at 8 years

nr/up to 18 years

Grievink 1993 8246466 (Nijmegen Otitis Media study) 9/1982-8/1983 Netherlands

NRCS, prospective

Not reported

. yes nr/7 years

Hu-2015-26429601 2014 US

NRCS, retrospective

No funding Conductive hearing loss caused by OME, preoperative audiometry performed no more than one month prior to the surgery, postoperative audiometry completed at two weeks and six to ten weeks following the procedure for

yes 1-18 excluded trisomy 21, mixed hearing loss, congenital cholesteatoma

3/10

C-6

Study Study design

Funding source

Inclusion criteria Tympanography

Hearing test

Age range

(y)

Subgroups Number of assessments/followup

duration (weeks) each patient

Hubbard 1985 4039792 1/1979-1/1979 U.S.

NRCS, prospective

Not reported

cleft palate, previous myringotomy

. 5-11 included cleft palate .

Kuşcu 2015 26545930 2008-2013 Turkey

NRCS, retrospective

No funding Patients operated in our university or in other centers and admitted to our university for further follow-up with a follow-up time of at least two years or more after palate reconstruction surgery were included in the study. OME diagnosis was confirmed with pneumatic otoscopy and tympanometry for the study.

yes yes included cleft palate nr/>=104

Li 2015 26281253a 2002-2012 China

NRCS, retrospective

Government

Patients with adenoid hypertrophy and OME admitted to the hospital during the study period, chronic OME diagnosed based on the diagnostic criteria in the Chinese guideline (tympanography type B or C, difference in air and bone conduction by pure tone hearing test)

yes yes included adenoid hypertrophy nr/52

Li 2015 26281253b 2002-2012 China

NRCS, retrospective

Government

Patients with cleft palate and OME admitted to the hospital during the study period, chronic OME diagnosed based on the diagnostic criteria in the Chinese guideline (tympanography type B or C, difference in air and bone conduction by pure

yes yes included cleft palate nr/52

C-7

Study Study design

Funding source

Inclusion criteria Tympanography

Hearing test

Age range

(y)

Subgroups Number of assessments/followup

duration (weeks) tone hearing test)

Niclasen-2016-27063746 1990 Danmark

NRCS, retrospective

No funding Aarhus Birth Cohort from 1990 and onwards, the primary exposure of the study was two items concerned with parent-reported episodes (4+) of OM and tympanostomy tubes insertion, respectively.

9-11

Peters 1994 8195687 8/1982-7/1983 Netherlands

NRCS, prospective

Not reported

. yes 364-416 weeks

Stenstrom 2005 16330739 1985-1989 Canada

NRCS, prospective

Academic/Hospital

long-standing middle ear effusion [>3 months

. yes 2.5-7 1/56

Yagi 1977 321716 Sudan

NRCS, prospective

Not reported

secretory otitis media; Clinical evidence of fluid in the middle ear in addition to the audiometric findings

. yes 3-12 nd/6 weeks

Yousaf 2012 23855103 6/2008-12/2011 Pakistan

NRCS, prospective

Not reported

X-Ray nasopharynx lateral view was taken to see if there were adenoids.

. yes 2-8 nd/144

Coyte 2001 11309633 1992-1997 Canada

NRCS, retrospective

Not reported

. 0-19

C-8

Study Study design

Funding source

Inclusion criteria Tympanography

Hearing test

Age range

(y)

Subgroups Number of assessments/followup

duration (weeks) Forquer 1982 6184891 U.S.

NRCS, retrospective

Not reported

chronic serous otitis media 0-9 excluded cleft palate, Pre-existing hearing loss, history of mastoiditis or cholesteatoma

.

Kadhim 2007 17279052 1981-2004 Australia

NRCS, retrospective

Not reported

.

Kobayashi 2012 22386274 1996-1999 Japan

NRCS, retrospective

Not reported

. included cleft palate every 6 months from 0-6 years of age, annually after 7 years of age

Marshak 1980 6778336 Israel

NRCS, retrospective

Not reported

chronic secretory otitis media yes 0-8 4 to 8/104 weeks

Motta 2006 17465378 1/1/2001-12/31/2001 Italy

NRCS, retrospective

Not reported

AAP definition (2004): Tympanic mucosa congestion, possibly with exudate, without acute infection; Recurrent febrile episodes related to adenotonsillar inflammation (>=2 episodes in previous 12 months), with OME or AOM. Underwent adenoidectomy; Recurrent febrile episodes related to adenotonsillar inflammation (>=2 episodes in previous 12 months), with OME or AOM. Underwent adenoidectomy

. 2-11 excluded other craniofacial anomalies, genetic syndromes

minimum 104

Reiter 2009

NRCS, retrosp

Not reported

OME lasting more than 3 months; atelectasis/tympanic

. yes 0-14 included cleft palate 12/312

C-9

Study Study design

Funding source

Inclusion criteria Tympanography

Hearing test

Age range

(y)

Subgroups Number of assessments/followup

duration (weeks) 19929085 Germany

ective membrane retraction pockets

Robson 1992 1431515 1976-1988 UK

NRCS, retrospective

Not reported

operated on by one plastic surgeon for cleft lip, cleft palate or a combination of cleft lip and palate

. included cleft palate

Schilder 1997 9372253 09/1982-08/1983 Netherlands

NRCS, retrospective

Government?

.

yes

2-4

nd/from 2-4 yo to 7-8 yo

Wolter 2012 22883987 1991-2009 Canada

NRCS, retrospective

Not reported

. yes 0.7-17 included primary ciliary dyskinesia

nr

Xu 2003 12930655 09/1997-05/2000 China

NRCS, retrospective

Government

. yes 1.3-10 included cleft palate 2/nd

Youssef 2013 24265883 03/2007-01/2009 Egypt

NRCS, retrospective

Not reported

bilateral OM, eligible for surgical intervention, no previous myringotomy or TT

yes nd/52

C-10

Table C2. Key Question 2 design Author Year

PMID Years of recruitment

Country

Design Number of participant

s

Age Range

(y)

Inclusion criteria Exclusion criteria

Casselbrant 1992 1565551 3/1981-1/1988 U.S.

RCT 264 0.6, 2.9 3 or more episodes of AOM during the preceding 6 months or 4 or more episodes during the preceding 12 months, but free of middle ear effusion at the time of entry

Exclusion criteria: potentially complicating or confounding conditions, e.g. asthma, chronic sinusitis or previous tonsillectomy or adenoidectomy

El-Sayed 1996 noPMID Saudi Arabia

RCT 68

0, 3

>= 3 attacks of acute otitis media diagnosed, documented and treated by their referring physician in the 6 month period prior to referral

Gonzalez 1986 3537596 1/1982-2/1983-12/1983-11/1985 U.S.

RCT 63 0.5, 10 >= 3 episodes of AOM during the past 6 months, or >=4 episodes in the past 18 months

Exclusion criteria: Down syndrome, cleft palate, previous tympanostomy tubes

Grindler 2014 24627408 1/2009-2/2012 U.S.

NRCS, prospective

1208 0.5, 2 Exclusion criteria: caregivers unable to provide consent; caregivers unable to complete the survey forms in English

Hammarén-Malmi 2005 15995051 03/2001-12/2002 Finland

RCT 12 months; ;

. as judged by examination with a pneumatic otoscope; >=3 episodes of acute otitis media during the preceding 6 months or ?5 episodes of acute otitis media during the preceding

excluded cleft palate, asthma, diabetes

C-11

Author Year PMID Years of

recruitment Country

Design Number of participant

s

Age Range

(y)

Inclusion criteria Exclusion criteria

Kujala 2012 22466327, 24445832 3/2002-6/2004 Finland

RCT 300 0, 2 at least 3 AOM episodes during the past 6 months Exclusion criteria: Cranial abnormalities, chronic otitis media with effusion, a prior adenoidectomy or tympanostomy tubes, documented immunological disorders or ongoing antimicrobial prophylaxis for a disease other than AOM

Mattila 2003 12578443 RCT 1996-1999 Finland

RCT 137 0.83, 2 >3-5 episodes within six months or 4-6 episodes during the last year; a visually abnormal membrane on a flat B-type tympanogram, signs of effusion in the middle ear cavity and symptoms that related to acute otitis

Mattila 2003 12578443 NRCS 1996-1999 Finland

NRCS, prospective

169 0.83, 2 >3-5 episodes within six months or 4-6 episodes during the last year; a visually abnormal membrane on a flat B-type tympanogram, signs of effusion in the middle ear cavity and symptoms that related to acute otitis

Table C3. Key Question 4 design Author Year PMID Date

Country

Study design

Age range (years)

Inclusion criteria No. assessments/plann

ed duration (weeks)

Becker 1987 3586818 4/1985-9/1985 U.S.

NRCS, prospective

All patients undergoing tympanostomy and insertion of ventilation tubes. Most cases were chronic otitis media with effusion unresponsive to medical management for 3 or more months. Any occasional indication was recurrent acute otitis media.

0

Cohen 1994 8289048 1990-1992

NRCS, prospective

3, 12 Underwent plastic ventillation tube insertion because of recurrent otitis media or serious otitis media complicated by impared hearing

78-130

C-12

Author Year PMID Date

Country

Study design

Age range (years)

Inclusion criteria No. assessments/plann

ed duration (weeks)

Israel

el Silimy 1986 3780019 UK

NRCS, prospective

4, 14 Grommets inserted, after myringotomy and aspiration of the middle ear contents, in the anterosuperior quadrant of the tympanic membrane. none

3/26

Francois-1992-1485779.pdf

NRCS Patients getting tubes a minimum of 3 months prior to summer vacation. nr/12-16

Goldstein 2005 15689760 7/1996-6/1999 U.S.

RCT 0.5, 6 Children undergoing tube insertion at the Children’s Hospital of Pittsburgh. bilateral myringotomy and tube insertion for recurrent AOM or chronic otitis media with effusion (OME). Exclusion: Children who were immunocompromised (immunodeficiency syndrome, AIDS or HIV-positive status, diabetes mellitus, undergoing chemotherapy, chronic steroid dependence), had a craniofacial syndrome or a history of a cleft palate, or had undergone prior ear surgery except for tympanostomy tube placement

12/52

Kaufmann 1999 10546304 1/1996-1/1997 Switzerland

NRCS, prospective

0.23, 0.67 Got tubes at the same clinic, but by different surgeons. every 8-12 weeks until tubes extruded

Konradsson-1986-3784716.pdf

NRCS (odd-even day assignment)

< 15 TT placed for chronic secretory otits media or recurrent acute otitis. nr/24

Parker 1993 8024107 12/1989-2/1991 U.S.

RCT Patients with tympanostomy tubes 4/52

Salata 1996 8607955 U.S.

NRCS, prospective

Children who were undergoing myringotomy with placement of tympanostomy tubes every 12 weeks until tubes extruded

Sharma 1986 3472335

NRCS, prospective

3, 11 Children with grommets, seen on first followup at 6 weeks. Until spontaneous

Smelt 1984 6538215 UK

NRCS, prospective

2, 15 The operations were done by the authors. A Shepard grommet was inserted into the antero-inferior quadrant of the drumhead if myringotomy liberated thick glue or copious thin fluid. This was done either as the only procedure or combined with tonsillectomy or adenotonsillectomy.

every 8 weeks until tubes extruded

Table 4. Key Question 5 design Study Study

design Age

range (y)

Inclusion criteria Exclusion criteria Assessment times/followup (weeks)

C-13

Study Study design

Age range

(y)

Inclusion criteria Exclusion criteria Assessment times/followup (weeks)

Dohar 1999 10326811

NRCS 1,12 Premenarchal if female; had patent TT with mucopurulent otorrhea of presumed bacterial origin for less than 3 weeks

Menarchal, otorrhea for 3 weeks or more 4 visits over 2.9 weeks

Dohar 2006 16880248 5/2003-5/2004 U.S., Finland

RCT 0.5, 12 Definition of otorrhea: clinical diagnosis of uncomplicated AOM with otorrhea >3 weeks duration

otorrhea present for ?3 weeks and those with acute or malignant otitis externa. Additional enrollment exclusions included known or suspected fungal or mycobacterial ear infections, a history of or active viral infections of the tympanic membrane, mastoiditis, or infections requiring systemic antibiotic therapy. Patients were also excluded for otologic surgery (except that confined to the tympanic membrane) in the previous year or if they presented with or had a history of diabetes, immunosuppressive disorders, acute or chronic renal disease, active hepatitis, chronic nasal obstruction and/or persistent rhinorrhea, complicating structural abnormalities, known or suspected quinolone hypersensitivity, and, in girls, menarche

4/3

Goldblatt 1998 10190709 U.S.

RCT 4+ recurrent acute otitis media (AOM) 4/3

Granath 2008 18565598 Sweden

RCT < 3 years

TT associated otorrhea in children with rAOM

Craniomaxillar malformation, chromosomal aberration, known immunological deficiency or other severe underlying disease

24

Heslop 2010 20979100 5/2003-5/2007 Chile

RCT 0, 10 secretory otitis media (SOM) for more than 3 months or recurrent acute otitis media (AOM)

non-Caucasians, otorrhea due to other ear diseases other diseases or handicaps, or treatment with systemic or local antibiotics during the preceding 3 weeks, taking topical or systemic steroids or nonsteroidal anti-inflammatory drugs

1

Roland 2003 14660913 3/2000-2/2001 U.S.

RCT 0.5, 12 Definition of otorrhea: clinical diagnosis of acute otitis media with visible otorrhea of 3 weeks duration or less, patent tympanostomy tube

fungal or mycobacterial ear infections, active herpes simplex, vaccinia, varicella, or overt viral infections of the tympanic membrane, mastoiditis or other suppurative noninfectious ear infections, chronic nasal obstruction or persistent rhinorrhea, a prior or current history of immunosuppressive disorders or immunosuppressive therapy, acute renal disorders, active hepatitis, diabetes, or conditions that may predispose to neurosensory hearing loss

4/3

C-14

Study Study design

Age range

(y)

Inclusion criteria Exclusion criteria Assessment times/followup (weeks)

Roland 2004 14702493 U.S.

RCT 0.5, 12 Definition of otorrhea: drainage visible to the parent or guardian of >3 weeks duration

otorrhea had been present for > ?3 weeks, acute or malignant otitis externa, known or suspected fungal or mycobacterial ear infections, a history of or active viral infection of the tympanic membrane, mastoiditis, or infections requiring systemic antibacterial therapy, requirement for otologic surgery (except that confined to the tympanic membrane) in the previous year or when they presented with or had a history of diabetes, immunosuppressive disorders, acute or chronic renal disease, active hepatitis, chronic nasal obstruction and/or persistent rhinorrhea, complicating structural abnormalities, known or suspected quinolone hypersensitivity, and, in girls, menarche.

4/3

Ruohola 1999 10190921 03/1996-05/1997 Denmark

RCT 0.5, 12 Definition of otorrhea: drainage started within 48 hours before examination at the study clinic

Down syndrome, Cleft palate, diabetes mellitus, known immunodeficiency, middle ear granulomatous tissue or polyp, TT or abx in preceding 2 weeks, otorrhea during preceding 4 weeks, steroids use, allergy to penicillin or amoxicillin

1/2

Ruohola 2003 12728089 09/1998-06/1999 Finland

RCT 0.6, 6 Definition of otorrhea: started within 48 hours before recruitment

Down syndrome, Cleft palate, granulation of polyp in the tympanic membrane, immunodeficiency, TT or antibiotics/steroid use in the preceding 2 weeks, TT in the preceding 4 weeks, allergy to penicillin,

2/3

Strachan 2000 10865480 UK

RCT Definition of otorrhea: a degree of discharge from the ear with ventilation tubes in-situ

2/3

van Dongen 2014 24552319 25896832 6/2009-5/2012 Netherlands

RCT 1, 10 otorrhea that had lasted for up to 7 days

Down syndrome, Cleft palate, craniofacial anomalies, immunodeficiency, temperature >38.5 C, received antibiotics during the previous 2 weeks, TT placed within the previous 2 weeks, had an episode of etorrhea in the previous 4 weeks, >=3 episodes in the previous 6 months, or >=4 episodes in the previous year

2/26

C-15

Appendix D. Arm Details Table D1. Key Question 1 arm details

Study Arm (Description) Antibiotic name, dose,

duration

Diagnostic criteria for AOM

Management of acute infections

Tube type

Augustsson 2006 16214225 Sweden

Tympanostomy tubes .

Augustsson 2006 16214225 Sweden

Control (those who were referred to an ENT-department from screening or from other doctors because of ear disease, usually SOM, but never so longstanding that they qualified for treatment with tympanostomy tubes up to 14 years of age)

.

Bernard 1991 1861917 Canada

Antibiotic prophylaxis sulfisoxazole, 75 mg/kg bid, 6 mo.

otomicroscopic findings (redness of the TM, absence of landmarks), acute -onset ear pair w/w/o fever or otorrhea

an oral non-sulfa-based antibiotics (usually amoxicillin)

.

Bernard 1991 1861917 Canada

Myringotomy+TT discharge from the ear and presence of pathogens commonly associated with AOM

an oral non-sulfa-based antibiotics (usually amoxicillin)

Reuter bobbin VTs for the 1st 10 pts, then Richard "T" VTs

Casselbrant 2009 19819563 1997-2005 U.S.

Myringotomy+TT amoxicillin, 40 mg/kg/day in two divided doses, 10 d.

. fever, earache or recent onset of ear tugging; and irritability; Otoscopic criteria: erythema and/or white opacification (other than from scarring) of the tympanic membrane, fullness or bulging of the tympanic membrane, white fluid level, and otorrhea from a perforation

Teflon Armstrong-type tympanostomy tube

D-1

Study Arm (Description) Antibiotic name, dose,

duration

Diagnostic criteria for AOM

Management of acute infections

Tube type

of a previously intact tympanic membrane.

Casselbrant 2009 19819563 1997-2005 U.S.

TT AND myringotomy AND adenoidectomy

amoxicillin, 40 mg/kg/day in two divided doses, 10 d.

. fever, earache or recent onset of ear tugging; and irritability; Otoscopic criteria: erythema and/or white opacification (other than from scarring) of the tympanic membrane, fullness or bulging of the tympanic membrane, white fluid level, and otorrhea from a perforation of a previously intact tympanic membrane.

Teflon Armstrong-type tympanostomy tube

Casselbrant 2009 19819563 1997-2005 U.S.

Myringotomy AND adenoidectomy amoxicillin, 40 mg/kg/day in two divided doses, 10 d.

. fever, earache or recent onset of ear tugging; and irritability; Otoscopic criteria: erythema and/or white opacification (other than from scarring) of the tympanic membrane, fullness or bulging of the tympanic membrane, white fluid level, and otorrhea from a perforation of a previously intact tympanic membrane.

.

Chaudhuri 2006 23120310 India

Antibiotic prophylaxis (Amoxicillin + carbocisteine)

Amoxicillin, 125 mg (infants), 250 mg (older children), 2 wks; carbocisteine, 5

.

D-2

Study Arm (Description) Antibiotic name, dose,

duration

Diagnostic criteria for AOM

Management of acute infections

Tube type

mL, 2 wks Chaudhuri 2006 23120310 India

TT + myringotomy +/- adenoidectoy (radial myringotomy in antero inferior quadrant of tympanic membrane with insertion of grommet with or without adenoidectomy under general anesthesia)

. grommet

Coyte 2001 11309633 1992-1997 Canada

TT (Tympanostomy tubes) .

Coyte 2001 11309633 1992-1997 Canada

TT AND adenoidectomy .

De Beer 2004 15224825 1982-1983 Netherland

TT (Tympanostomy tubes) parents had reported events of otalgia with fever and/or otorrhea during the screening at 2 to 4 years of age, in the period between both studies (4 to 8 years), and/or at the examination at 8 years

De Beer 2004 15224825 1982-1983 Netherland

Control (No Tympanostomy tubes) parents had reported events of otalgia with fever and/or otorrhea during the screening at 2 to 4 years of age, in the period between both studies (4 to 8 years), and/or at the examination at 8 years

Forquer 1982 6184891 U.S.

Treated medically, then surgically . collar-button or mesh-type tubes

D-3

Study Arm (Description) Antibiotic name, dose,

duration

Diagnostic criteria for AOM

Management of acute infections

Tube type

Forquer 1982 6184891 U.S.

Initially treated surgically collar-button or mesh-type tubes

Gates 1985 4040338 (University of Texas Otitis Media Study Center) U.S.

TT (Tympanostomy tubes) . Shepherd type with an internal opening of 1.1 mm

Gates 1985 4040338 (University of Texas Otitis Media Study Center) U.S.

Myringotomy (Myringotomy only) .

Gates 1987 3683478 4/1980-6/1984 U.S.

TT (Tympanostomy tubes) . effusion + inflammation Shepard-type

Gates 1987 3683478 4/1980-6/1984 U.S.

TT AND adenoidectomy . effusion + inflammation Shepard-type

Gates 1987 3683478 4/1980-6/1984 U.S.

Myringotomy (Myringotomy only) . effusion + inflammation

Gates 1987 3683478 4/1980-6/1984 U.S.

Myringotomy AND adenoidectomy . effusion + inflammation

Gates 1988 3336263

Myringotomy+TT (placement of TT after bilateral myringotomy)

. Shepard-type

D-4

Study Arm (Description) Antibiotic name, dose,

duration

Diagnostic criteria for AOM

Management of acute infections

Tube type

U.S. Gates 1988 3336263 U.S.

TT AND myringotomy AND adenoidectomy

. Shepard-type

Gates 1989 2492178 U.S.

Myringotomy (Myringotomy only) erythromycin ethyl succinate. 50 mg/kg, 10 d.; sulfisoxazole, 150 mg/kg, 10 d.

.

Gates 1989 2492178 U.S.

Myringotomy+TT erythromycin ethyl succinate. 50 mg/kg, 10 d.; sulfisoxazole, 150 mg/kg, 10 d.

. Shepard-type

Gates 1989 2492178 U.S.

Myringotomy AND adenoidectomy erythromycin ethyl succinate. 50 mg/kg, 10 d.; sulfisoxazole, 150 mg/kg, 10 d.

.

Gates 1989 2492178 U.S.

TT AND myringotomy AND adenoidectomy

erythromycin ethyl succinate. 50 mg/kg, 10 d.; sulfisoxazole, 150 mg/kg, 10 d.

. Shepard-type

Hammarén-Malmi 2005 15995051 03/2001-12/2002 Finland

TT (Tympanostomy tubes) . antibiotics

Hammarén-Malmi 2005 15995051 03/2001-

TT AND adenoidectomy . antibiotics

D-5

Study Arm (Description) Antibiotic name, dose,

duration

Diagnostic criteria for AOM

Management of acute infections

Tube type

12/2002 Finland Hu-2015-26429601 2014 US

TT (Tympanostomy tubes) collar button tube

Hu-2015-26429601 2014 US

TT and adenotonsillectomy collar button tube

Hubbard 1985 4039792 1/1979-1/1979 U.S.

Early TT (University center) . tympanostomy tube

Hubbard 1985 4039792 1/1979-1/1979 U.S.

Late TT (Hospital center) . tympanostomy tube

Kadhim 2007 17279052 1981-2004 Australia

TT (Tympanostomy tubes) .

Kadhim 2007 17279052 1981-2004 Australia

TT AND adenoidectomy .

Kobayashi 2012 22386274 1996-1999 Japan

Control (no TT) .

Kobayashi 2012 22386274 1996-1999 Japan

TT (Tympanostomy tubes) . the Grommet-type ventilation tube (Nagashima, inner diameter 1.0 mm) or the

D-6

Study Arm (Description) Antibiotic name, dose,

duration

Diagnostic criteria for AOM

Management of acute infections

Tube type

Bobbin-type ventilation tube (Koken B type, inner diameter, 1.6 mm)

Kuşcu 2015 26545930 2008-2013 Turkey

Early routine TT (Tympanostomy tubes)

grommet

Kuşcu 2015 26545930 2008-2013 Turkey

TT during follow-up grommet

Kuşcu 2015 26545930 2008-2013 Turkey

No TT

Li 2015 26281253a 2002-2012 China

Myringotomy (Myringotomy only) Cefathiamidine, 30 mg/kg, 5 days

Li 2015 26281253a 2002-2012 China

Myringotomy+TT Cefathiamidine, 30 mg/kg, 5 days

Li 2015 26281253b 2002-2012 China

Myringotomy (Myringotomy only) Cefathiamidine, 30 mg/kg, 5 days

Li 2015 26281253b 2002-2012 China

Myringotomy+TT Cefathiamidine, 30 mg/kg, 5 days

Mandel 1989

Control (unspecified intervantion) usually amoxicillin, 14

at least one symptom (fever, otalgia, irritability)

an antimicrobial drug, usually amoxicillin, and a

.

D-7

Study Arm (Description) Antibiotic name, dose,

duration

Diagnostic criteria for AOM

Management of acute infections

Tube type

2789777a 09/1979-09/1984 U.S.

d. and one sign (bulging or fullness of the tympanic membrane, white fluid level, acute perforation with otorrhea) of acute infection

decongestant-antihistamine combination for 14 days for recurrent OME

Mandel 1989 2789777a 09/1979-09/1984 U.S.

Myringotomy (Myringotomy only) usually amoxicillin, 14 d.

at least one symptom (fever, otalgia, irritability) and one sign (bulging or fullness of the tympanic membrane, white fluid level, acute perforation with otorrhea) of acute infection

an antimicrobial drug, usually amoxicillin, and a decongestant-antihistamine combination for 14 days for recurrent OME

.

Mandel 1989 2789777a 09/1979-09/1984 U.S.

Myringotomy+TT usually amoxicillin, 14 d.

at least one symptom (fever, otalgia, irritability) and one sign (bulging or fullness of the tympanic membrane, white fluid level, acute perforation with otorrhea) of acute infection

an antimicrobial drug, usually amoxicillin, and a decongestant-antihistamine combination for 14 days for recurrent OME

Teflon Armstrong-type tympanostomy tube

Mandel 1989 2789777b 09/1979-09/1984 U.S.

Myringotomy (Myringotomy only) usually amoxicillin, 14 d.

at least one symptom (fever, otalgia, irritability) and one sign (bulging or fullness of the tympanic membrane, white fluid level, acute perforation with otorrhea) of acute infection

an antimicrobial drug, usually amoxicillin, and a decongestant-antihistamine combination for 14 days for recurrent OME

.

Mandel 1989 2789777b 09/1979-09/1984 U.S.

Myringotomy+TT usually amoxicillin, 14 d.

at least one symptom (fever, otalgia, irritability) and one sign (bulging or fullness of the tympanic membrane, white fluid level, acute perforation with otorrhea) of acute infection

an antimicrobial drug, usually amoxicillin, and a decongestant-antihistamine combination for 14 days for recurrent OME

Teflon Armstrong-type tympanostomy tube

Mandel 1992 1565550 11/1981-06/1987

Watchful waiting (no surgery) . at least one symptom (fever, otalgia, irritability), and one sign (bulging or fullness of the tympanic membrane, white fluid

.

D-8

Study Arm (Description) Antibiotic name, dose,

duration

Diagnostic criteria for AOM

Management of acute infections

Tube type

U.S. level, acute perforation with otorrhea) of acute infection

Mandel 1992 1565550 11/1981-06/1987 U.S.

Myringotomy (Myringotomy only) . at least one symptom (fever, otalgia, irritability), and one sign (bulging or fullness of the tympanic membrane, white fluid level, acute perforation with otorrhea) of acute infection

.

Mandel 1992 1565550 11/1981-06/1987 U.S.

Myringotomy+TT . at least one symptom (fever, otalgia, irritability), and one sign (bulging or fullness of the tympanic membrane, white fluid level, acute perforation with otorrhea) of acute infection

.

Marshak 1980 6778336 Israel

TT (Tympanostomy tubes) .

Marshak 1980 6778336 Israel

Myringotomy AND adenoidectomy .

Maw 1999 10459904, Hall-2009-19260880, Wilks-2000-10944051 4/1991-12/1992 UK

TT (Tympanostomy tubes within 6 weeks)

. confirmation of bilateral OME by otoscopy and tympanometry

.

Maw 1999 10459904, Hall-2009-19260880, Wilks-2000-10944051

Watchful waiting (for 9 months then tubes if needed)

. confirmation of bilateral OME by otoscopy and tympanometry

.

D-9

Study Arm (Description) Antibiotic name, dose,

duration

Diagnostic criteria for AOM

Management of acute infections

Tube type

4/1991-12/1992 UK Motta 2006 17465378 1/1/2001-12/31/2001 Italy

TT AND adenoidectomy .

Motta 2006 17465378 1/1/2001-12/31/2001 Italy

Adenoidectomy (Adenoidectomy only) .

MRC Multicentre Otitis Media Study Group 2012 (TARGET) 22443163 15373863 12680834 4/1994-10/1998 UK

TT AND adenoidectomy . Shepard

MRC Multicentre Otitis Media Study Group 2012 (TARGET) 22443163, 2004 15373863 4/1994-1/1998 UK

TT (Tympanostomy tubes) . Shepard

MRC Multicentre Otitis Media

Medical Management

D-10

Study Arm (Description) Antibiotic name, dose,

duration

Diagnostic criteria for AOM

Management of acute infections

Tube type

Study Group 2012 (TARGET) 22443163, 2004 15373863 4/1994-1/1998 UK Niclasen-2016-27063746 1990 Danmark

No TT

Niclasen-2016-27063746 1990 Danmark

TT (Tympanostomy tubes)

Nguyen 2004 15126745 01/1998-01/2003 Canada

TT (Tympanostomy tubes) 10 d. pressure equalization tubes

Nguyen 2004 15126745 01/1998-01/2003 Canada

TT AND adenoidectomy 10 d. pressure equalization tubes

Paradise 2001 11309632, 2005 16093466, 2003 12897272, 2007

Early TT . Antimicrobial drugs were routinely prescribed for episodes of acute otitis media

Armstrong

D-11

Study Arm (Description) Antibiotic name, dose,

duration

Diagnostic criteria for AOM

Management of acute infections

Tube type

17229952, Johnston2004 15231974 6/1991-12/1995 U.S. Paradise 2001 11309632, 2005 16093466, 2003 12897272, 2007 17229952, Johnston2004 15231974 6/1991-12/1995 U.S.

Late TT (six months later if bilateral effusion persisted or nine months later if unilateral effusion persisted)

. Antimicrobial drugs were routinely prescribed for episodes of acute otitis media

Armstrong

Paradise 2001 11309632, 2005 16093466, 2003 12897272, 2007 17229952, Johnston2004 15231974 6/1991-12/1995 U.S.

Randomization withheld . Armstrong (optional tube insertion)

Paradise Not eligible for randomization . .

D-12

Study Arm (Description) Antibiotic name, dose,

duration

Diagnostic criteria for AOM

Management of acute infections

Tube type

2001 11309632, 2005 16093466, 2003 12897272, 2007 17229952, Johnston2004 15231974 6/1991-12/1995 U.S. Popova 2010 20399511 2007-2009 Bulgaria

TT AND myringotomy AND adenoidectomy

. Diagnosis of AOM required the finding of middle ear effusion on otoscopy with at least one symptom, i.e., fever, earache or recent ear tugging, irritability and one sign of inflammation, i.e., erythema and/or white opacification of the tympanic membrane, otorrhea from a perforation of a previously intact tympanic membrane. For proper differentiation of otorrhea episodes from AOM episodes we defined otorrhea as mucous or mucopurulent discharge from the ear with no symptoms of acute inflammation.

. fluoroplastic Donaldson grommets (Micromedics, Inc.)

Popova 2010 20399511

Myringotomy AND adenoidectomy . Diagnosis of AOM required the finding of middle ear effusion on otoscopy with

.

D-13

Study Arm (Description) Antibiotic name, dose,

duration

Diagnostic criteria for AOM

Management of acute infections

Tube type

2007-2009 Bulgaria

at least one symptom, i.e., fever, earache or recent ear tugging, irritability and one sign of inflammation, i.e., erythema and/or white opacification of the tympanic membrane, otorrhea from a perforation of a previously intact tympanic membrane. For proper differentiation of otorrhea episodes from AOM episodes we defined otorrhea as mucous or mucopurulent discharge from the ear with no symptoms of acute inflammation.

Rach 1991 2070526 Netherlands

TT (Tympanostomy tubes) . silicone ventilating tubes, Donaldson design

.

Rach 1991 2070526 Netherlands

Control (unspecified intervantion) .

Reiter 2009 19929085 Germany

palate cleft repair + TT (cleft palate or lip)

. gold grommet

Reiter 2009 19929085 Germany

palate cleft repair (cleft palate or lip) .

Robson 1992 1431515 1976-1988 UK

TT (Tympanostomy tubes) . 10 (26.3%) had long term ventilation tubes ('Goode tubes')

Robson 1992 1431515

Control (conservative treatment) .

D-14

Study Arm (Description) Antibiotic name, dose,

duration

Diagnostic criteria for AOM

Management of acute infections

Tube type

1976-1988 UK Rovers 2000 10969126, 2001 11124783, 2001 11409855, 2001 11470387, Ingels 2005 16429748, Hartman 2001 11735817 01/1996-04/1997 Netherlands

TT (Tympanostomy tubes; some pts received andenoidectomy, equally distributed)

. Bevel Bobbins, Entermed BV, The Netherlands; grommets

Rovers 2000 10969126, 2001 11124783, 2001 11409855, 2001 11470387, Ingels 2005 16429748, Hartman 2001 1173581701/1996-04/1997 Netherlands

Watchful waiting (no surgery; some pts received andenoidectomy, equally distributed)

.

Schilder 1997 TT .

D-15

Study Arm (Description) Antibiotic name, dose,

duration

Diagnostic criteria for AOM

Management of acute infections

Tube type

9372253 09/1982-08/1983 Netherlands Schilder 1997 9372253 09/1982-08/1983 Netherlands control (no TT) .

Stenstrom 2005 16330739 1985-1989 Canada

TT (Tympanostomy tubes) . 50 (83%) of 60 patients received T-type VTs

Stenstrom 2005 16330739 1985-1989 Canada

Control (medical treatment (low-dose sulfisoxazole for 6 months)

.

Velepic 2011 21397957 2004-2009 Croatia

TT AND adenoidectomy .

Velepic 2011 21397957 2004-2009 Croatia

Adenoidectomy (Adenoidectomy only) .

Vlastos 2011 21205368 5/2007-5/2008 Greece

TT AND adenoidectomy . Shepard type

Vlastos 2011

Myringotomy AND adenoidectomy .

D-16

Study Arm (Description) Antibiotic name, dose,

duration

Diagnostic criteria for AOM

Management of acute infections

Tube type

21205368 5/2007-5/2008 Greece Wolter 2012 22883987 1991-2009 Canada

TT (Tympanostomy tubes) .

Wolter 2012 22883987 1991-2009 Canada

Treated medically (periodic antibiotics or hearing aids)

.

Xu 2003 12930655 09/1997-05/2000 China

palate cleft repair (cleft palate or lip) .

Xu 2003 12930655 09/1997-05/2000 China

palate cleft repair + TT (cleft palate or lip)

.

Yagi 1977 321716 Sudan

Adenoidectomy (Adenoidectomy only) .

Yagi 1977 321716 Sudan

TT AND myringotomy AND adenoidectomy

.

Yousaf 2012 23855103 6/2008-12/2011 Pakistan

TT (Tympanostomy tubes) 10 d.

Yousaf 2012 23855103 6/2008-

Myringotomy (Myringotomy only) 10 d.

D-17

Study Arm (Description) Antibiotic name, dose,

duration

Diagnostic criteria for AOM

Management of acute infections

Tube type

12/2011 Pakistan Youssef 2013 24265883 03/2007-01/2009 Egypt

TT + myringotomy +/- adenoidectoy .

Youssef 2013 24265883 03/2007-01/2009 Egypt

Laser myringotomy +/- adenoidectomy .

Table D2. Key Question 2 arm details Study Arm (description) Tube type

Casselbrant 1992 1565551 3/1981-1/1988 U.S. prophylaxis (Amoxicillin) Casselbrant 1992 1565551 3/1981-1/1988 U.S. Tympanostomy tubes Teflon Armstrong-

type El-Sayed 1996 Saudi Arabia prophylaxis (sulfamethoxazole and trimethoprim) . El-Sayed 1996 Saudi Arabia Tympanostomy tubes Gonzalez 1986 3537596 1/1982-2/1983-12/1983-11/1985 U.S.

prophylaxis (sulfisoxazole) .

Gonzalez 1986 3537596 1/1982-2/1983-12/1983-11/1985 U.S.

Tympanostomy tubes Paparella

Gonzalez 1986 3537596 1/1982-2/1983-12/1983-11/1985 U.S.

no treatment

Grindler 2014 24627408 1/2009-2/2012 U.S. Tympanostomy tubes Grindler 2014 24627408 1/2009-2/2012 U.S. control

Hammaren-Malmi 2005 15995051 TT Donaldson silicon

Hammaren-Malmi 2005 15995051 TT & Adenoidectomy Donaldson silicon

D-18

Study Arm (description) Tube type Kujala 2012 22466327, 24445832 3/2002-6/2004 Finland TT & adenoidectomy

Kujala 2012 22466327, 24445832 3/2002-6/2004 Finland No treatment Mattila 2003 12578443 RCT 1996-1999 Finland TT AND adenoidectomy Mattila 2003 12578443 RCT 1996-1999 Finland Tympanostomy tubes Mattila 2003 12578443 NRCS 1996-1999 Finland TT AND adenoidectomy Mattila 2003 12578443 NRCS 1996-1999 Finland Tympanostomy tubes

Table D3. Key Question 4 arm details Study Arm Comments/Notes about interventions

Becker 1987 3586818 4/1985-9/1985 U.S.

ear plugs Silicon putty ear plugs: no restrictions on frequency, duration, location or type of swimming

Becker 1987 3586818 4/1985-9/1985 U.S.

no ear plugs no restrictions on frequency, duration, location or type of swimming

Becker 1987 3586818 4/1985-9/1985 U.S.

nonswimming custom-fitted molded ear plugs

Cohen 1994 8289048 1990-1992 Israel

swimming participated in swimming 4-6 times a week; in chlorinated pool water or seawater without restrictions; swimming season lasted April through September; duration of swimming was 1/2-2 hours/day; mandatory use of neomycin-polymyxin-hydrocortizone eardrops at bedtime on the day that the child had been swimming.

Cohen 1994 8289048 1990-1992 Israel

nonswimming

el Silimy 1986 3780019 UK swimming children swam with ears unprotected on average once every 2 weeks for an average of three-quarters of an hour. This swimming was in Council indoor heated swimming pools

el Silimy 1986 3780019 UK nonswimming Francois 1992 1485779 France

nonswimming

Francois 1992 1485779 France

swimming Swam in pool, the Atlantic or Mediteranean

Goldstein 2005 15689760 7/1996-6/1999 U.S.

ear plugs A soft, plastic, prefabricated ear plug (Doc’s Proplugs, International Aquatic Trades, Inc., Santa Cruz, CA) or, if their ear canals were too small, with a moldable silicone ear plug (Insta-Putty, Insta-Mold Products, Inc., Oaks, PA).

Goldstein 2005 15689760 7/1996-6/1999 U.S.

no ear plugs

Kaufmann 1999 10546304 1/1996-1/1997 Switzerland

ear plugs ear plugs, bathing caps, and/or water-absorbent padding

D-19

Study Arm Comments/Notes about interventions Kaufmann 1999 10546304 1/1996-1/1997 Switzerland

no precautions

Konràdsson 1986 3784716 6/1983-11/1983 Sweden

no precautions

Konràdsson 1986 3784716 6/1983-11/1983 Sweden

ear protection War cotton wadding in ear(s) and bathing cap when bathing

Parker 1993 8024107 12/1989-2/1991 U.S.

swimming patients were allowed to swim and bathe without precautions

Parker 1993 8024107 12/1989-2/1991 U.S.

nonswimming patients were instructed not to swim or submerge their heads while bathing

Salata 1996 8607955 U.S. no precautions children who were allowed to swim without ear protection or postexposure medication

Salata 1996 8607955 U.S. ear drops children who were allowed to swim without any ear protection (on days when they were exposed to water, their parents were to instill three drops of a suspension that contained polymyxin B sulfate, neomycin sulfate, and hydrocortisone into each ear before bedtime)

Salata 1996 8607955 U.S. ear plugs children who were fitted with prefabricated ear molds and instructed to use the ear molds whenever they were swimming

Salata 1996 8607955 U.S. nonswimming children who were assigned to groups 1 through 3 but never actually went swimming during the study period

Sharma 1986 3472335 UK swimmers Swimming in chlorinated pools allowed (6 weeks after TT placed), avoid jumping from a high board and swimming with a cold

Sharma 1986 3472335 UK nonswimmers No swimming Smelt 1984 6538215 UK swimming Surface swimming in a clean, chlorinated, outdoor swimming pool without earplugs

or other ear protection. The patients spent about 1 hour swimming in the pool, and diving was prohibited during swimming

Smelt 1984 6538215 UK swimming Surface swimming in a clean, chlorinated, outdoor swimming pool without earplugs or other ear protection. The patients spent about 1 hour swimming in the pool, and diving was prohibited during swimming

Smelt 1984 6538215 UK nonswimming

D-20

Table D4. Key Question 5 arm details Study Arm Antibiotic name, dose

Dohar 1999 10326811 U.S. antibiotic drop Ofloxacin, 0.25 ml twice daily, 10 days Dohar 1999 10326811 U.S. historic controls at the discretion of the treating physician (not Ofloxacin), , Dohar 1999 10326811 U.S. current usual treatment at the discretion of the treating physician (not Ofloxacin), , Dohar 2006 16880248 5/2003-5/2004 U.S., Finland

antibiotic drop Ciprodex Sterile Otic Suspension, 4 drops twice daily, 7 days

Dohar 2006 16880248 5/2003-5/2004 U.S., Finland

oral antibiotic Augmentin ES-600, 90 mg/kg per day divided every 12 hours, 10 days

Goldblatt 1998 10190709 U.S. antibiotic drop ofloxacin, 40 mg/kg, 10 days Goldblatt 1998 10190709 U.S. oral antibiotic amoxicillin/cavulanate, 0.25 ml, 10 days Granath 2008 18565598 -2/1998-12/2002 Sweden

antibiotic drop hydrocortisone + oxytetracycline + polymyxine B, NR, 5-7 days

Granath 2008 18565598 -2/1998-12/2002 Sweden

antibiotic drop + oral antibiotic

hydrocortisone + oxytetracycline + polymyxine B; amoxicillin, NR, 5-7 days

Heslop 2010 20979100 5/2003-5/2007 Chile

oral antibiotic amoxicillin, 25 to 50 mg/kg/d divided into three daily doses, 1 week

Heslop 2010 20979100 5/2003-5/2007 Chile

Saline

Roland 2003 14660913 3/2000-2/2001 U.S.

antibiotic-glucocorticoid drops

Ciprofloxacin, ciprofloxacin 0.3% plus dexamethasone 0.1% otic suspension, 7 days

Roland 2003 14660913 3/2000-2/2001 U.S.

antibiotic drop Ciprofloxacin, ciprofloxacin 0.3% ophthalmic solution, 7 days

Roland 2004 14702493 U.S. antibiotic-glucocorticoid drops

Ciprofloxacin/Dexamethasone, 4 drops twice daily, 7 days

Roland 2004 14702493 U.S. antibiotic drop Ofloxacin, 5 drops twice daily, 10 days Strachan 2000 10865480 UK antibiotic-glucocorticoid

drops Otosporin, 3 drops, three times a day, 7-14 days

van Dongen 2014 24552319 25896832 6/2009-5/2012 Netherlands

antibiotic-glucocorticoid drops

bacicoline-B, five drops, tid, 7 days

van Dongen 2014 24552319 25896832 6/2009-5/2012 Netherlands

oral antibiotic amoxicillin– clavulanate suspension, 30 mg of amoxicillin and 7.5 mg of clavulanate per kilogram of body weight, 7 days

D-21

Appendix E. Baseline Characteristics Table E1. Key Question 1 baselines

Study Arm Age (y), mean

(range)

Age of

onset (y)

Average hearing

level mean (SD)

No. of siblings

mean (SD)

No. of OME

episodes mean

Hearing loss mean

Male gender n/N (%)

Poverty/low SES n/N (%)

Cigarette smoke

exposure n/N (%)

Daycare n/N (%)

Augustsson 2006 16214225

TT 61/61 (100)

Augustsson 2006 16214225

Control 173/173 (100)

Bernard 1991 1861918

Myringotomy+TT

4.7 30.7 2.9 34/60 (56.7)

Bernard 1991 1861919

Antibiotic prophylaxis

5 29.6 3.0 34/65 (52.3)

Casselbrant 2009 19819564

Myringotomy+TT

[2, 3.9] 19/32 (59.4)

Casselbrant 2009 19819565

TT AND myringotomy AND adenoidectomy

[2, 3.9] 24/32 (75.0)

Casselbrant 2009 19819566

Myringotomy AND adenoidectomy

[2, 3.9] 22/34 (64.7)

Chaudhuri 2006 23120310

Total [0, 12]

Coyte 2001 11309633

TT Median: 2 [IQR 1, 5]

16296/26714 (61)

Coyte 2001 11309634

TT AND adenoidectomy

Median: 4 [IQR 3, 6]

2475/4125 (60)

De Beer 2004 15224825

TT 24/51 (47)

De Beer 2004 15224825

Control 63/132 (48)

Gates 1989 2492179

Myringotomy 2.3 0.43 (with otitis media)

65/107 (61) 52/107 (49)

Gates 1989 2492180

Myringotomy+TT

2.2 0.48 (with otitis media)

75/129 (58) 70/129 (54)

E-1

Study Arm Age (y), mean

(range)

Age of

onset (y)

Average hearing

level mean (SD)

No. of siblings

mean (SD)

No. of OME

episodes mean

Hearing loss mean

Male gender n/N (%)

Poverty/low SES n/N (%)

Cigarette smoke

exposure n/N (%)

Daycare n/N (%)

Gates 1989 2492181

Myringotomy AND adenoidectomy

2.3 0.46 (with otitis media)

77/130 (59) 73/130 (56)

Gates 1989 2492182

TT AND myringotomy AND adenoidectomy

2.3 0.49 (with otitis media)

73/125 (58) 63/125 (50)

Gates 1988 3336263

Total [4, 8]

Gates 1988 3336267

TT AND myringotomy AND adenoidectomy

Gates 1987 3683478

Myringotomy 69% 4.0-6.5 2.3 65/107 (61) 52/107 (49)

Gates 1987 3683479

TT 69% 4.0-6.5 2.2 75/129 (58) 70/129 (54)

Gates 1987 3683480

Myringotomy AND adenoidectomy

73% 4.0-6.5 2.3 77/130 (59) 73/130 (56)

Gates 1987 3683481

TT AND adenoidectomy

74% 4.0-6.5 2.3 73/125 (58) 63/125 (50)

Gates 1985 4040338

TT

Gates 1985 4040339

Myringotomy

Grievink 1993 8246466

Control 7.75 (2) 80/151 (53%)

Grievink 1993 8246466

TT -1.9 23/37 (62.2%)

Hall 2009 19260880

Total 3 [1.25, 4.67]

Hall 2009 19260881

Early TT 49/88 (56)

Hall 2009 19260882

Watchful waiting

44/74 (59)

Hammarén-Malmi 2006

TT [1, 4] 1.0 (0.9) 56/96 (58.3)

48/96 (50.0)

Hammarén-Malmi 2007

TT AND adenoidectomy

[1, 4] 1.1 (1.0) 51/102 (50.0)

56/102 (54.9)

Hu-2015- Total [0.83, 10] 20/34 (59)

E-2

Study Arm Age (y), mean

(range)

Age of

onset (y)

Average hearing

level mean (SD)

No. of siblings

mean (SD)

No. of OME

episodes mean

Hearing loss mean

Male gender n/N (%)

Poverty/low SES n/N (%)

Cigarette smoke

exposure n/N (%)

Daycare n/N (%)

26429601 Hubbard 1985 4039792

Early TT

Hubbard 1985 4039793

Late TT

Kadhim 2007 17279052

TT (Tympanostomy tubes)

Kadhim 2007 17279052

TT AND adenoidectomy

Kobayashi 2012 22386275

TT

Kobayashi 2012 22386276

Control

Kremer 1979 456299

Total [0, >7] 152/243 (62.4)

Kuşcu 2015 26545930

Early routine TT

6.9 (4.3) 29/67 (43.3)

Kuşcu 2015 26545930

TT at follow-up 9.1 (3.7) 13/22 (59.1)

Kuşcu 2015 26545930

No TT 15.8 (8.9) 37/65 (56.9)

Li 2015 26281253a 2002-2012 China

Total 5.9 [3, 14] 109/208 (52.4)

Li 2015 26281253b 2002-2012 China

Total 5.7 [3, 14] 215/319 (67.4)

Mandel 1992 1565550

Watchful waiting

[0.58, 12] 22/35 (62.9)

16/33 (48.5)

Mandel 1992 1565550

Myringotomy [0.58, 12] 25/39 (64.1)

22/36 (61.1)

Mandel 1992 1565550

Myringotomy+TT

[0.58, 12] 27/37 (73.0)

14/35 (40.0)

Mandel 1989 2789777a

Control [0.58, 12] 22/29 (75.9)

11/29 (37.9)

Mandel 1989 2789777a

Myringotomy [0.58, 12] 12/27 (44.4)

6/27 (22.2)

Mandel 1989 2789777a

Myringotomy+TT

[0.58, 12] 20/30 (66.7)

11/30 (36.7)

E-3

Study Arm Age (y), mean

(range)

Age of

onset (y)

Average hearing

level mean (SD)

No. of siblings

mean (SD)

No. of OME

episodes mean

Hearing loss mean

Male gender n/N (%)

Poverty/low SES n/N (%)

Cigarette smoke

exposure n/N (%)

Daycare n/N (%)

Mandel 1989 2789777b

Myringotomy [0.58, 12] 10/12 (83.3)

2/12 (16.7)

Mandel 1989 2789777b

Myringotomy+TT

[0.58, 12] 9/11 (81.8) 1/11 (9.1)

Marshak 1980 6778336

Total [0, 8]

Maw 1999 10459904, Hall-2009-19260880, Wilks-2000-10944051

TT 2.96 (0.84) [1.17, 4.62]

13% 1, 47% 2, 30% >=3

40/88 (47)

Maw 1999 10459904, Hall-2009-19260880, Wilks-2000-10944051

Watchful waiting

2.93 (0.87) [1.31, 4.69]

17% 1, 39% 2, 44% >=3

35/72 (49)

Motta 2006 17465378

Total 66% <6 [2, 11]

114/193 (59)

MRC Multicentre Otitis Media Study Group (TARGET) 22443163 12680834 15373863

TT AND adenoidectomy

5.4 (0.86) 31.7 (6.4) Mean reported hearing difficulty – RHD (sd) 14.0 (4.2)

61/128 (48) 81/125 (65)

46/115 (40)

120/120 (100)

MRC Multicentre Otitis Media Study Group 22443163 12680834 15373863

TT 5.2 (0.85) 32.2 (6.0) Mean reported hearing difficulty – RHD (sd) 14.4 (4.1)

60/126 (48) 84/126 (67)

35/110 (32)

121/123 (98)

MRC Multicentre Otitis Media Study Group (TARGET) 22443163 12680834 15373863

Watchful waiting

5.2 (0.87) 33.5 (6.4) Mean reported hearing difficulty – RHD (sd) 13.6 (4.5)

62/122 (51) 82/122 (67)

29/101 (29)

110/110 (100)

Niclasen-2016-27063746

No TT >= 4 288/569 (50.6)

Maternal: 250/569 (44.0); paternal

0-3 years 521/569

E-4

Study Arm Age (y), mean

(range)

Age of

onset (y)

Average hearing

level mean (SD)

No. of siblings

mean (SD)

No. of OME

episodes mean

Hearing loss mean

Male gender n/N (%)

Poverty/low SES n/N (%)

Cigarette smoke

exposure n/N (%)

Daycare n/N (%)

261/569 (45.8)

(91.5); <3-6 years 558/569 (98.1)

Niclasen-2016-27063746

TT (Tympanostomy tubes)

>= 4 577/999 (57.8)

Maternal: 452/999 (45.2); paternal 508/999 (50.9)

0-3 years 924/999 (92.5); 3-6 years 982/999 (98.3)

Nguyen 2004 15126745

TT 3.4 [1.5, 9.5]

24/40 (60)

Nguyen 2004 15126745

TT AND adenoidectomy

4.5 [1.5, 9.5]

13/23 (57)

Paradise 2001 11309632, 2005 16093466, 2003 12897272, 2007 17229952, Johnston2004 15231974

Early TT 39.7% 1, 46.1% 2, 14.2% 3

115/204 (56.4)

Paradise 2001 11309632, 2005 16093466, 2003 12897272, 2007 17229952, Johnston2004 15231974

Late TT 40.9% 1, 47.7% 2, 11.4% 3

112/193 (58.0)

Peters 1994 8195687

Control 7.75 (2) 80/151 (53)

Peters 1994 8195687

TT 7.75 (1.9) 23/37 (62.2)

Popova 2010 20399511

TT AND myringotomy AND adenoidectomy

5 (1) [3.5, 7.2]

22/42 (52.4)

19/42 (45) 40/42 (95)

E-5

Study Arm Age (y), mean

(range)

Age of

onset (y)

Average hearing

level mean (SD)

No. of siblings

mean (SD)

No. of OME

episodes mean

Hearing loss mean

Male gender n/N (%)

Poverty/low SES n/N (%)

Cigarette smoke

exposure n/N (%)

Daycare n/N (%)

Popova 2010 20399511

Myringotomy AND adenoidectomy

5.1 (3.8, 6.3)

20/36 (55.6)

31/36 (86) 36/36 (100)

Rach 1991 2070526

TT [2, 4]

Rach 1991 2070526

Control [2, 4]

Reiter 2009 19929085

Total 8.5 (2.2) [0, 14]

28/53 (52.8)

Robson 1992 1431515

TT 6.3 [2, 13] 22/38 (57.9)

Robson 1992 1431515

Control 5.2 [0.5, 12] 14/32 (43.8)

Rovers 2000 10969126, 2001 11124783, 2001 11409855, 2001 11470387, Ingels 2005 16429748, Hartman 2001 11735817

Total 1.62 (1.3) 0.75 44.9 (0.82) best ear

110/187 (58.8)

49/187 (26.1)

Rovers 2000 10969126, 2001 11124783, 2001 11409855, 2001 11470387, Ingels 2005 16429748, Hartman 2001 11735817

TT 1.625 (1.7) 0.75 46.4 (1.1) best ear [IQR 44.2, 48.6]

55/93 (59.1)

Rovers 2000 10969126, 2001 11124783, 2001 11409855, 2001 11470387, Ingels 2005 16429748, Hartman 2001 11735817

Watchful waiting

1.62 (1.9) 0.75 43.4 (1.2) best ear [IQR 41.0, 45.8]

55/94 (58.5)

Stenstrom 2005 16330739

Control 12.3 (3.8) [8, 16]

3.1 (1.6) Mean hearing loss at

14/27 (52) 14/27 (52) 15/27 (56)

E-6

Study Arm Age (y), mean

(range)

Age of

onset (y)

Average hearing

level mean (SD)

No. of siblings

mean (SD)

No. of OME

episodes mean

Hearing loss mean

Male gender n/N (%)

Poverty/low SES n/N (%)

Cigarette smoke

exposure n/N (%)

Daycare n/N (%)

entry into RCT, PTA at 0.5, 1, 2, 4 kHz: mean: 33.4, sd: 11.9

Stenstrom 2005 16330739

TT 11.6 (4.3) [8, 16]

1.9 (1.8) Mean hearing loss at entry into RCT, PTA at 0.5, 1, 2, 4 kHz: mean: 28.7, sd: 13

23/38 (60) 16/38 (42) 25/38 (66)

Velepic 2011 21397957

TT AND adenoidectomy

5.56

Velepic 2011 21397957

Adenoidectomy

5.44

Vlastos 2011 21205368

TT AND adenoidectomy

4.6 (1.1) [3, 7]

31.2 (3.9) [21, 39]

14/25 (56)

Vlastos 2011 21205368

Myringotomy AND adenoidectomy

4.4 (1.1) [3, 7]

32.7 (0.72) [27, 37]

15/27 (56)

Wolter 2012 22883987

Total Median: 6 [0.7, 17]

Median: 5.74

Xu 2003 12930655

palate cleft repair

43.9

Xu 2003 12930655

palate cleft repair + TT

4.8 [0.5, 10] 35.9

Yagi 1977 321716 Total Median: 6 [3, 12]

100% >20dB

Yousaf 2012 23855103

Total [2, 8] 38/62 (61.3)

Youssef 2013 24265883

Total 7.4 (2.0) 44/86 (51.1)

Youssef 2013 TT + 7.8 (1.5)

E-7

Study Arm Age (y), mean

(range)

Age of

onset (y)

Average hearing

level mean (SD)

No. of siblings

mean (SD)

No. of OME

episodes mean

Hearing loss mean

Male gender n/N (%)

Poverty/low SES n/N (%)

Cigarette smoke

exposure n/N (%)

Daycare n/N (%)

24265883 myringotomy +/- adenoidectoy

Youssef 2013 24265883

Laser myringotomy +/- adenoidectomy

6.9 (2.3)

Schilder 1997 9372253 TT [2,4 ]

14.0 (12.8)

7/13 (53.8)

Schilder 1997 9372253 control (no TT) [2,4 ]

8.4 (7.7)

8/14 (57.1)

Table E2. Key Question 2 baselines

Study Arm Age (y), mean (range) No. of OME episodes, mean

Males n/N (%)

In daycare n/N (%)

Casselbrant 1992 1565551

Antibiotic prophylaxis (amoxicilin) 43.3% 0.58-1.25, 40.0% 1.33-2.08, 16.7% 2.17-3*

Casselbrant 1992 1565551

Placebo 43.2% 0.58-1.25, 37.5% 1.33-2.08, 19.3% 2.17-3*

Casselbrant 1992 1565551

TT 45.3% 0.58-1.25, 34.9% 1.33-2.08, 19.8% 2.17-3*

El-Sayed 1996 TT 1.66 17/31 (48.6)

El-Sayed 1996 Antibiotic prophylaxis (sulfamethoxazole and trimethoprim)

1.64

Gonzalez 1986 3537596

TT 1.68

Gonzalez 1986 3537596

Antibiotic prophylaxis (sulfisoxazole) 1.55

Gonzalez 1986 3537596

Placebo 1.39

Grindler 2014 24627408

Total 1.23 (0.38) 652/1208 (54.0)

603/1006 (61.2)

Hammarén-Malmi 2006 TT [1,4] 56/96 (58.3)

Hammarén-Malmi 2006 TT & Adenoidectomy [1,4] 51/102 (50.0)

Kujala 2012 22466327, 24445832

TT 1.34 (0.33) 6.7 36/100 (36)

E-8

Study Arm Age (y), mean (range) No. of OME episodes, mean

Males n/N (%)

In daycare n/N (%)

Kujala 2012 22466327, 24445832

TT & Adenoidectomy 1.48 (0.36) 6.3 41/100 (41)

Kujala 2012 22466327, 24445832

Control 1.33 (0.32) 6.4 48/100 (48)

Mattila 2003 12578443 RCT

Total 1.42 3.5 86/137 (62.8)

35/137 (25.5)

Mattila 2003 12578443 RCT

TT + adenoidectomy 1.39 3.5 47/74 (64) 17/74 (22)

Mattila 2003 12578443 RCT

TT 1.45 3.4 39/63 (62) 18/63 (27)

Mattila 2003 12578443 NRCS

Total 1.45 3.5 91/169 (53.8)

43/169 (25.4)

Mattila 2003 12578443 NRCS

TT + adenoidectomy 1.46 3.5 64/124 (52)

31/124 (25)

Mattila 2003 12578443 NRCS

TT 1.44 3.5 27/45 (60) 12/45 (27)

*age given only in % in certain ranges

Table E3. Key Question 4 baselines Study Arm Age (y), mean

(range) Males n/N

(%) Hx of adenoidectomy

n/N (%) Hx of tonsilectomy

n/N (%) Other

Becker 1987 3586818 nonswimming

4.9 (1, 14) 24/30 Sheehy Teflon collar button tubes

Becker 1987 3586819 ear plugs 6.3 (2, 14) 17/23 (17) Sheehy Teflon collar button tubes

Becker 1987 3586820 no ear plugs 5,9 (1.5, 13) 10/32 (31) Sheehy Teflon collar button tubes

Cohen 1994 8289048 nonswimming

(3, 12) 11/20 (55)

Cohen 1994 8289049 swimming (3, 12) 12/22 (54.5)

el Silimy 1986 3780019

nonswimming

7 (4, 14) 24/41 (58.5) 18/41 (43.9) 7/41 (17.1) 16/41 (39%) bilateral grommets

el Silimy 1986 3780019

swimming 7 (4, 14) 25/45 (55.6) 20/45 (44.4) 7/45 (15.6) 18/45 (40%) bilateral grommets

Francois 1992 1485779.

non-swimming

5.58 (overall)

Francois 1992 1485779.

swimming

E-9

Study Arm Age (y), mean (range)

Males n/N (%)

Hx of adenoidectomy n/N (%)

Hx of tonsilectomy n/N (%)

Other

Goldstein 2005 15689760

ear plugs 79%<=3 (0.5, 6)* 59/103 (57) 24/103 (23)

Goldstein 2005 15689760

no ear plugs 81%<=3 (0.5, 6)* 60/98 (61) 24/98 (24)

Kaufmann 1999 10546304

Total 15/86 (18) 17/86 (20)

Kaufmann 1999 10546305

no precautions

5.3 (1.2, 15.6) 30/47 (63)

Kaufmann 1999 10546306

ear plugs 5.8 (1.3, 12.3) 11/16 (67)

Konradsson 1986 3784716

nonswimming

(1, 15) nr nr

Konradsson 1986 3784716

swimming

Parker 1993 8024107 nonswimming

3.1 (0.58, 9)

Parker 1993 8024107 swimming 3.1 (0.25, 8)

Salata 1996 8607955 Total 2.67 (0.5, 12) 238/399 (59.6)

80/399 (20)

Salata 1996 8607956 no precautions

Salata 1996 8607957 ear drops

Salata 1996 8607958 ear plugs

Salata 1996 8607959 nonswimming

Sharma 1986 3472335

non-swimmers

nr nr

Sharma 1986 3472335

swimmers nr nr

Smelt 1984 6538215 Total 39 had grommet resinsertions

Smelt 1984 6538215 swimming

* age given only in % below/above 3 years

Table E4. Key Question 5 baselines Study Arm Age (y), mean

(SD) [range] No. of previous

episodes of otorrhea, mean

(range)

Males n/N (%)

Cigarette smoke

exposure n/N (%)

Daycare n/N

(%)

Bilateral

otorrhea n/N (%)

E-10

Study Arm Age (y), mean (SD) [range]

No. of previous episodes of

otorrhea, mean (range)

Males n/N (%)

Cigarette smoke

exposure n/N (%)

Daycare n/N

(%)

Bilateral

otorrhea n/N (%)

Dohar 1999 10326811

antibiotic drop 3.6 (2.7) 143/89 (62)

Dohar 1999 10326811

historic controls

3.6 (2.5) 309/175 (57)

Dohar 1999 10326811

current usual treatment

3.7 (2.5) 68/45 (67)

Dohar 2006 16880248

antibiotic drop 59% <2* 39/20 (51) 39/5 (13)

Dohar 2006 16880248

oral antibiotic 56% <2* 41/22 (54) 41/11 (27)

Goldblatt 1998 10190709

antibiotic drop 3.7 (2.46)

Goldblatt 1998 10190709

oral antibiotic 3.5 (2.62, p=0.521)

Heslop 2010 20979100

antibiotic drop 0.9 [0.6-9] (all) 40/68 (59) (all)

Heslop 2010 20979100

oral antibiotic

Heslop 2010 20979100

saline rinse

Roland 2003 14660913

antibiotic-glucocorticoid drops

2.57 (2.54) [0, 12] 87/46 (52.9)

87/22 (25.3)

Roland 2003 14660913

antibiotic drop 2.26 (2.21) [0, 11] 80/41 (51.3)

80/14 (17.5)

Roland 2004 (14702493, 15195060, Waycaster 2004_no PMID)

antibiotic-glucocorticoid drops

49.2%<2, 49.8% 2-11, 1.0% >11*

297/172 (57.9)

Roland 2004 14702493

antibiotic drop 49.0%<2, 51.0% 2-11*

302/201 (66.6)

Ruohola 1999 10190921

oral antibiotics and glucosteroids

[1.0,10.0] 23/14 (61)

Ruohola 1999 10190921

oral antibiotics and palcebo

[1.0,5.8] 27/14 (52)

E-11

Study Arm Age (y), mean (SD) [range]

No. of previous episodes of

otorrhea, mean (range)

Males n/N (%)

Cigarette smoke

exposure n/N (%)

Daycare n/N

(%)

Bilateral

otorrhea n/N (%)

Ruohola 2003 12728089

oral antibiotic 2.25 (1.08) 3.5 (IQR 3, 4.25)

34/24 (71) 34/19 (56) 34/22 (65)

Ruohola 2003 12728089

oral placebo 1.75 (0.92) 3 (IQR 2, 4) 32/20 (63) 32/16 (50) 32/18 (56)

Strachan 2000 10865480

antibiotic-glucocorticoid drops

7.3 [2,25] (all)

Strachan 2000 10865480

antibiotic-glucocorticoid spray

van Dongen 2014 24552319 (25896832)

antibiotic-glucocorticoid drops

4.6 (2.1) (0, 5) 76/50 (66) 76/13 (17) 32/29 (91)

76/14 (18)

van Dongen 2014 24552319 (25896832)

oral antibiotic 4.4 (2.0) (0, 5) 77/40 (52) 77/4 (5) 33/27 (82)

77/11 (14)

van Dongen 2014 24552319 (25896832)

watchful waiting

4.4 (2.0) (0, 3) 77/43 (56) 77/9 (12) 31/25 (81)

77/13 (17)

* age given only in % below/above threshold.

E-12

Appendix F. Risk of Bias

Table F1. Risk of bias, RCTs

Stud

y

Ran

dom

se

quen

ce

gene

ratio

n

Allo

catio

n co

ncea

lmen

t

Blin

ding

of

part

icip

ants

Blin

ding

of

pers

onne

l/ca

re p

rovi

ders

Blin

ding

of

outc

ome

asse

ssor

Inco

mpl

ete

outc

ome

data

Sele

ctiv

e R

epor

ting

Inte

ntio

n-to

-tr

eat-

anal

ysis

Gro

up

sim

ilarit

y at

ba

selin

e

Co-

inte

rven

tions

Bernard 1991 1861917 Unclear Unclear High High Low Low Unclear Low Low Unclear Casselbrant 2009 19819563 Unclear Unclear High High Unclear High Unclear Low Low Unclear D'Eredità 2006 16406076 Unclear Unclear High High High Low High Low Unclear Low Gates 1987 3683478 Low Low High High Low Low Low Low Low Unclear Mandel 1989 2789777 Unclear Unclear High High Unclear Low Unclear High Low Unclear Mandel 1992 1565550 Unclear Unclear High High High Low Unclear Unclear Low Unclear Maw 1999 10459904 Unclear Unclear High High High High Low Low Low Unclear MRC Multicenter Otitis Media Study Group 2003 12680834 High High High High Unclear High Unclear High Unclear Unclear

MRC Multicentre Otitis Media Study Group 2012 22443163 High Unclear High High High Low Unclear Low Low Unclear

Nguyen 2004 15126745 Unclear Unclear High High High Low Unclear Low Low Unclear Paradise 2001 11309632 Low Low High High High Low Low Low Low Unclear Popova 2010 20399511 Unclear Unclear Unclear Unclear Unclear Low Low High Low Low Rach 1991 2070526 High Unclear High High High High Unclear High Unclear High Rovers 2000 10969126 Unclear Unclear High High Unclear Low Unclear Low Low Low Velepic 2011 21397957 Unclear Unclear High Unclear Unclear Low Low Low Low Low Vlastos 2011 21205368 Low Unclear High High Unclear High Low Low Low Low Casselbrant 1992 1565551 Unclear Unclear High High High High Low Low Low Low El-Sayed 1996 Unclear Unclear High High High Low Unclear Low Low Low Gonzalez 1986 3537596 Low Unclear High High High Low Unclear Low Low High Hammaren-Malmi 2005 15995051 Unclear Unclear High High Unclear High Low Low Low Low Hammarén-Malmi 2005 15995051 Unclear Unclear High High Unclear Low Unclear Low Low Unclear Kujala 2012 22466327, 24445832 Low Low High High High Low Low Low Low Unclear Mattila 2003 12578443 Unclear Low High High High Low Unclear Low Low High Goldstein 2005 15689760 Unclear Unclear High Unclear Low Low Low Low Low Unclear Parker 1993 8024107 Low Unclear High Unclear Unclear High Unclear High Unclear Unclear Dohar 2006 16880248 Low Low High High Low Low Low Low Low Low Goldblatt 1998 10190709 Low High High High Low Low Low Low Low Low Granath 2008 18565598 Low High High High High Low Low Low Low Low Heslop 2010 20979100 Unclear Low Low Low Low Unclear Low Low Low Low

F-1

Stud

y

Ran

dom

se

quen

ce

gene

ratio

n

Allo

catio

n co

ncea

lmen

t

Blin

ding

of

part

icip

ants

Blin

ding

of

pers

onne

l/ca

re p

rovi

ders

Blin

ding

of

outc

ome

asse

ssor

Inco

mpl

ete

outc

ome

data

Sele

ctiv

e R

epor

ting

Inte

ntio

n-to

-tr

eat-

anal

ysis

Gro

up

sim

ilarit

y at

ba

selin

e

Co-

inte

rven

tions

Roland 2003 14660913 Unclear Unclear Low Unclear Unclear Low Low Low Low Low Roland 2004 14702493 Unclear Unclear High High Low High Low High Low Low Ruohola 1999 10190921 Low Low Low Low Low Low Unclear Low Low Low Ruohola 2003 12728089 Low Low Low Low Low Low Unclear Low Low Low Strachan 2000, 10865480 Low Low High Low Low Low Low Low Unclear Low van Dongen 2014 24552319 Low Low High High Low Low Low Low Low Unclear

Table F2. Risk of bias, NRCSs

Stud

y

Is th

e ca

se d

efin

ition

ad

equa

te?

Rep

rese

ntat

iven

ess

of

the

case

s

Sele

ctio

n of

Con

trol

s

Def

initi

on o

f Con

trol

s

Asc

erta

inm

ent o

f Ex

posu

re

Sam

e m

etho

d of

as

cert

ainm

ent f

or c

ases

an

d co

ntro

ls

Non

-Res

pons

e ra

te

Allo

catio

n co

ncea

lmen

t

Dro

pout

rate

<20

per

cent

Blin

ded

patie

nt

Blin

ded

outc

ome

asse

ssm

ent

ITT

App

t. st

atis

tical

ana

lysi

s

If m

ultic

ente

r, w

as th

is

acco

unte

d fo

r in

anal

ysis

? W

ere

pote

ntia

l co

nfou

nder

s pr

oper

ly

acco

unte

d fo

r?

Cle

ar re

port

ing

with

no

disc

repa

ncie

s

Wer

e el

igib

ility

crit

eria

cl

ear?

Was

sel

ectio

n bi

as

likel

y?

Wer

e in

terv

entio

ns

adeq

uate

ly d

escr

ibed

?

Li 2015 26281253 Yes

Potential for selection biases or not stated

Hospital controls

No TT, no accumulation of fluid or serous fluid in the middle ear

No description

Yes Non respondents described

No No No NA No No No Yes No Yes

Tian 2015 26103659 Yes

Potential for selection biases or not stated

Hospital controls no TT Surgical

records Yes Non respondents described

Not reported

No No NA No No Yes Yes No No

Coyte 2001 11309633

Yes

Potential for selection biases or not stated

Hospital controls TT only

Written self report or medical record only

Yes Same rate for both groups

Na Yes No No No Yes No Yes Yes Yes No Yes

De Beer 2004 15224825

Yes Birth cohort OM score

OM+ highest tercile, not treated with TT

Prospective cohort Yes Low Yes No Yes Yes Yes No Yes

Forquer 1982 6184891

Unsure

Potential for selection biases or not stated

Hospital controls

Medical treatment (underwent medical treatment but not surgery for VT insertion)

Written self report or medical record only

Yes Same rate for both groups

Na Yes No No No No Na No No Yes Yes No

Grievink 1993 8246466

Yes

Consecutive or obviously representative series of cases*

Community controls*

OME but no TT

Written self report or medical record

Yes

Rate different and no designation

Na No No No No Yes Na Yes Yes Yes Yes Yes

F-2

only

Hu 2015 26429601

Potential for selection biases or not stated

Hospital controls TT only

Medical record review

Yes Unlcear No Yes Yes Yes Yes

Hubbard 1985 4039792

Unsure

Potential for selection biases or not stated

No description

No description of source

No description

Yes Same rate for both groups*

Na Yes No No Yes Yes Yes Yes No No No Yes

Kadhim 2007 17279052

No

Potential for selection biases or not stated

Hospital controls TT

Written self report or medical record only

Yes Same rate for both groups

Na No No No No Yes Na Yes Yes No No Yes

Kobayashi 2012 22386274

Yes

Potential for selection biases or not stated

Hospital controls no TT

No description

unclear

Non respondents described

Na Yes No No No Yes Na No Yes No Yes No

Kuşcu-2015-26545930.pdf

Yes

Potential for selection biases or not stated

Hospital controls

Late TT, never TT insertion

Medical record review

Yes Unclear No No Yes Yes Unclear Yes

Marshak 1980 6778336

Yes

Potential for selection biases or not stated

No description

No description of source

No description

Yes Same rate for both groups*

No No No No No Yes Na Nd No No No No

Motta 2006 17465378

Yes

Consecutive or obviously representative series of cases*

Community controls (Appropriate controls)

No TT, otherwise same surgery

Secure record (eg surgical records)*

Yes No No No Yes Yes No No

Niclasen 2016 27063746

No

Parent report. Unclear defiinition of OM

Self report 4+ incidences of OM without TT

Parental report Yes Unclear Yes Yes No Uncle

ar No

Peters 1994 8195687

Yes

Consecutive or obviously representative series of cases*

Community controls*

OME but no TT uncle

ar Na No No Nd No No Na No No Yes Yes No

Reiter 2009 19929085

Yes

Consecutive or obviously representative series of cases*

Hospital controls no TT

Written self report or medical record only (Case notes)

Yes Same rate for both groups*

Na Yes No Nd Na No Na No Yes Yes Yes No

Robson 1992 1431515

Yes

Potential for selection biases or not stated

Hospital controls

No tubes (Undergone surgery for cleft palate but did not have tubes inserted)

Written self report or medical record only (Case notes)

Yes Same rate for both groups*

Na Yes No No Nd No Na No No Yes Yes Yes

Schilder 1997 9372253

Yes

Consecutive or obviously representative series of cases*

No description no TT uncle

ar

unknown relative non-response rate

Na unclear No Nd Yes No unclear Yes Yes Yes no No

Stenstrom 2005 16330739

Yes Potential for selection biases or

Hospital controls

medical treatment (underwent

based off an RCT Yes

Same rate for both groups*

Nd No Nd Yes No Yes Na Yes Yes Yes Yes Yes

F-3

not stated medical treatment but not surgery for VT insertion)

Wolter 2012 22883987

No

Potential for selection biases or not stated

Hospital controls no TT Yes

Same rate for both groups*

No Yes No No Nd No Na No No No Yes No

Xu 2003 12930655 No

Potential for selection biases or not stated

Hospital controls no TT

no description

Same rate for both groups*

Na unclear No Nd Yes No Na No Yes No Yes No

Xu 2003 12930655 No

Potential for selection biases or not stated

Hospital controls no TT

No description

no description

Non respondents decribed

Not Applicable

No No Unclear Yes No Yes No Yes No

Yagi 1977 321716 Yes

Potential for selection biases or not stated

Hospital controls

no TT (only adenoidectomy)

unclear

Same rate for both groups*

Na Yes No No Yes No Na No Yes Yes Yes Yes

Yousaf 2012 23855103

Yes

Potential for selection biases or not stated

No description

No TT (medical management)

unclear

Same rate for both groups*

Na No Nd Nd No No Na No Yes Yes No No

Youssef 2013 24265883

Yes

Potential for selection biases or not stated

Hospital controls no TT uncle

ar

Non respondents described

Na Yes No Nd Nd No Na No Yes Yes Yes Yes

Grindler 2014 24627408

No

Potential for selection biases or not stated

Hospital controls

no TT insertion

Secure record)* Yes

unknown relative non-response rate

Not Applicable

Not Applicable

No No No Yes No Yes No Yes No Yes

Becker 1987 3586818

Yes

Potential for selection biases or not stated

parental choice

Parental choice

Written self report or medical record only

Yes

unknown relative non-response rate

Not Applicable

No No No

No analysis done.

Not Applicable

Not Applicable

Yes Yes Yes Yes No

Cohen 1994 8289048

Yes

Potential for selection biases or not stated

same cohort of tubes

same cohort of tubes, but nonswimmers

Written self report or medical record only

Yes Same rate for both groups*

Not Applicable

Yes No No

No analysis done.

Not Applicable

Not Applicable

Yes Yes No Yes No

el Silimy 1986 3780019

Yes

Potential for selection biases or not stated

same surgical cohort

nonswimmers

Written self report or medical record only

Yes Same rate for both groups*

Not Applicable

Yes No No

No analysis done.

Not Applicable

Not Applicable

Yes Yes No Yes Yes

Francois 1992 1485779

Potential for selection biases or not stated

Parental and patient choice - observational only

Children who did not swim

Parental retrospective report

Yes

Unknown relative non-response rate

Yes No No Yes No Yes No

Kaufmann 1999 10546304

Yes

Consecutive or obviously representative series of cases*

same cohort

no water protection

Written self report or medical record only

Yes Same rate for both groups*

Yes No No Yes Yes Not Applicable

Yes Yes Yes No Yes Yes

Konradsson 1986 3784716

Yes Even-odd randomization

Same surgical cohort

Children not given intructions to avoid swimming

Unclear Yes 11% No Yes No No Unclear No No No Yes Yes No

F-4

Salata 1996 8607955

Yes

Consecutive or obviously representative series of cases*

parent selection

recieved differnt prophylaxis

Written self report or medical record only

Yes

unknown relative non-response rate

Not Applicable

No No No Yes Yes Yes Yes Yes

unclear - high dropout

Yes Yes

Sharma 1986 3472335

Yes Parental choice

Parental choice

Chldren whose parents chose to let them swim

Unclear Yes Unclear No No No Yes Yes No

Smelt 1984 6538215

Yes unclear same surgical cohort

nonswimmers

Written self report or medical record only

Yes unclear

Not Applicable

No No Unclear

Not Appiicable

No No No No No No No

Dohar 1999 10326811

Yes

Consecutive or obviously representative series of cases*

Hospital controls

historical and concurrent with the same dx

Secure record (eg surgical records)*

Yes Same rate for both groups*

Not Applicable

No No No No No No No Yes Yes Yes No

F-5

Appendix G. Patient-Centered and Quality of Life Outcomes

Table G1. Patient-centered and quality of life outcomes Study author, years

PMIDs Age Interventions No. analyzed

Outcome type

Outcome Favors If significant, net difference or OR (95%CI)

P between groups NS = not significant at alpha = 0.05

Paradise, 2001, 2003, 2004, 2005, 2007

11309632, 16093466, 12897272, 17229952, 15231974, 12690269

3 years early treatment 206 cognitive McCarthy General Cognitive index delayed NS

delayed treatment

196

4 years early treatment 202-204 delayed NS delayed

treatment 193

3 years early treatment 206 verbal McCarthy Verbal Subscale delayed NS delayed

treatment 196

4 years early treatment 202-204 delayed NS delayed

treatment 193

3 years early treatment 206 cognitive McCarthy Perceptual Performance Subscale

delayed NS

delayed treatment

196

4 years early treatment 202-204 delayed NS delayed

treatment 193

3 years early treatment 206 cognitive McCarthy Quantitative Subscale delayed NS delayed

treatment 196

4 years early treatment 202-204 delayed NS delayed

treatment 193

3 years early treatment 206 verbal Peabody Picture Vocabulary Test–Revised

neither NS

delayed 196

G-1

Study author, years

PMIDs Age Interventions No. analyzed

Outcome type

Outcome Favors If significant, net difference or OR (95%CI)

P between groups NS = not significant at alpha = 0.05

treatment 4 years early treatment 202-204 delayed NS delayed

treatment 193

6 years early treatment 201 neither NS delayed

treatment 194

randomization consent withheld

101

not eligible for randomization

233

3 years early treatment 206 verbal Number of Different Words delayed NS delayed

treatment 196

4 years early treatment 202-204 delayed NS delayed

treatment 193

6 years early treatment 201 early NS delayed

treatment 194

randomization consent withheld

101

not eligible for randomization

233

3 years early treatment 206 verbal Mean Length of Utterance in Morphemes

delayed NS

delayed treatment

196

4 years early treatment 202-204 neither NS delayed

treatment 193

6 years early treatment 201 early NS delayed

treatment 194

randomization consent withheld

101

not eligible for randomization

233

G-2

Study author, years

PMIDs Age Interventions No. analyzed

Outcome type

Outcome Favors If significant, net difference or OR (95%CI)

P between groups NS = not significant at alpha = 0.05

3 years early treatment 206 verbal Percentage of Consonants Correct–Revised

delayed NS

delayed treatment

196

4 years early treatment 202-204 delayed NS delayed

treatment 193

6 years early treatment 201 neither NS delayed

treatment 194

randomization consent withheld

101

not eligible for randomization

233

4 years early treatment 202-204 verbal Nonword repetition test delayed -3.4 (-6.2, -0.7) <0.05 delayed

treatment 193

6 years early treatment 201 delayed -2 (-4.1, 0.1) <0.05 delayed

treatment 194

randomization consent withheld

101

not eligible for randomization

233

3 years early treatment 206 QOL Parenting Stress Index - parental distress subscale

delayed NS

delayed treatment

196

4 years early treatment 202-204 early NS delayed

treatment 193

6 years early treatment 201 delayed NS delayed

treatment 194

randomization consent withheld

101

not eligible for randomization

233

G-3

Study author, years

PMIDs Age Interventions No. analyzed

Outcome type

Outcome Favors If significant, net difference or OR (95%CI)

P between groups NS = not significant at alpha = 0.05

3 years early treatment 206 QOL Parenting Stress Index - parent-child dysfunction subscale

neither NS

delayed treatment

196

4 years early treatment 202-204 early NS delayed

treatment 193

6 years early treatment 201 neither NS delayed

treatment 194

randomization consent withheld

101

not eligible for randomization

233

3 years early treatment 206 QOL Parenting Stress Index - difficult child subscale

delayed NS

delayed treatment

196

4 years early treatment 202-204 delayed NS delayed

treatment 193

6 years early treatment 201 neither NS delayed

treatment 194

randomization consent withheld

101

not eligible for randomization

233

3 years early treatment 206 QOL Parenting Stress Index - total stress

delayed NS

delayed treatment

196

4 years early treatment 202-204 early NS delayed

treatment 193

6 years early treatment 201 neither NS delayed

treatment 194

G-4

Study author, years

PMIDs Age Interventions No. analyzed

Outcome type

Outcome Favors If significant, net difference or OR (95%CI)

P between groups NS = not significant at alpha = 0.05

randomization consent withheld

101

not eligible for randomization

233

3 years early treatment 206 Behavior Child Behavior Checklist - anxious/depressed scale

neither NS

delayed treatment

196

4 years early treatment 202-204 early NS delayed

treatment 193

6 years early treatment 201 neither NS delayed

treatment 194

randomization consent withheld

101

not eligible for randomization

233

3 years early treatment 206 Behavior Child Behavior Checklist - withdrawn scale

early NS

delayed treatment

196

4 years early treatment 202-204 early NS delayed

treatment 193

6 years early treatment 201 early NS delayed

treatment 194

randomization consent withheld

101

not eligible for randomization

233

3 years early treatment 206 Behavior Child Behavior Checklist - sleep problems scale

neither NS

delayed treatment

196

3 years early treatment 206 Behavior Child Behavior Checklist - somatic problems scale

early NS

delayed 196

G-5

Study author, years

PMIDs Age Interventions No. analyzed

Outcome type

Outcome Favors If significant, net difference or OR (95%CI)

P between groups NS = not significant at alpha = 0.05

treatment 4 years early treatment 202-204 early NS delayed

treatment 193

6 years early treatment 201 neither NS delayed

treatment 194

randomization consent withheld

101

not eligible for randomization

233

3 years early treatment 206 Behavior Child Behavior Checklist - aggression scale

early NS

delayed treatment

196

4 years early treatment 202-204 early NS delayed

treatment 193

6 years early treatment 201 early NS delayed

treatment 194

randomization consent withheld

101

not eligible for randomization

233

3 years early treatment 206 Behavior Child Behavior Checklist - delinquent/destructive scale

early NS

delayed treatment

196

4 years early treatment 202-204 early NS delayed

treatment 193

6 years early treatment 201 early NS delayed

treatment 194

randomization consent withheld

101

not eligible for 233

G-6

Study author, years

PMIDs Age Interventions No. analyzed

Outcome type

Outcome Favors If significant, net difference or OR (95%CI)

P between groups NS = not significant at alpha = 0.05

randomization 3 years early treatment 206 Behavior Child Behavior Checklist - total

problems early NS

delayed treatment

196

4 years early treatment 202-204 early NS delayed

treatment 193

9-11 years

early treatment 194 early 2 (0.1, 4.8) <0.05

delayed treatment

196

randomization consent withheld

127

not eligible for randomization

223

4 years early treatment 202-204 Behavior Child Behavior Checklist - social problems

early NS

delayed treatment

193

6 years early treatment 201 neither NS delayed

treatment 194

randomization consent withheld

101

not eligible for randomization

233

4 years early treatment 202-204 Behavior Child Behavior Checklist - thought problems

early NS

delayed treatment

193

6 years early treatment 201 neither NS delayed

treatment 194

randomization consent withheld

101

not eligible for randomization

233

4 years early treatment 202-204 Behavior Child Behavior Checklist - attention early NS

G-7

Study author, years

PMIDs Age Interventions No. analyzed

Outcome type

Outcome Favors If significant, net difference or OR (95%CI)

P between groups NS = not significant at alpha = 0.05

problems delayed

treatment 193

6 years early treatment 201 neither NS delayed

treatment 194

randomization consent withheld

101

not eligible for randomization

233

6 years early treatment 201 verbal Screening Test for Auditory Processing Disorders

delayed NS

delayed treatment

194

randomization consent withheld

101

not eligible for randomization

233

6 years early treatment 201 cognitive Wechsler Intelligence Scale for Children - full scale IQ

neither NS

delayed treatment

194

randomization consent withheld

101

not eligible for randomization

233

9-11 years

early treatment 195 not eligible

NS

delayed treatment

196

randomization consent withheld

127

not eligible for randomization

223

6 years early treatment 201 cognitive Wechsler Intelligence Scale for Children - Verbal IQ

neither NS

delayed treatment

194

randomization 101

G-8

Study author, years

PMIDs Age Interventions No. analyzed

Outcome type

Outcome Favors If significant, net difference or OR (95%CI)

P between groups NS = not significant at alpha = 0.05

consent withheld not eligible for

randomization 233

6 years early treatment 201 cognitive Wechsler Intelligence Scale for Children - Performance IQ

delayed NS

delayed treatment

194

randomization consent withheld

101

not eligible for randomization

233

9-11 years

early treatment 195 cognitive Woodcock Reading Mastery Tests, revised, normative updated version - word identification subtest

delayed/not eligible

NS

delayed treatment

196

randomization consent withheld

127

not eligible for randomization

223

9-11 years

early treatment 195 cognitive Woodcock Reading Mastery Tests, revised, normative updated version - word attack subtest

delayed/not eligible

NS

delayed treatment

196

randomization consent withheld

127

not eligible for randomization

223

9-11 years

early treatment 195 cognitive Woodcock Reading Mastery Tests, revised, normative updated version - passage comprehension subtest

delayed/not eligible

NS

delayed treatment

196

randomization consent withheld

127

not eligible for randomization

223

grade 3 (9)

early treatment 37 verbal Oral Reading Fluency Test delayed NS

G-9

Study author, years

PMIDs Age Interventions No. analyzed

Outcome type

Outcome Favors If significant, net difference or OR (95%CI)

P between groups NS = not significant at alpha = 0.05

delayed treatment

37

randomization consent withheld

28

not eligible for randomization

2

grade 4 (9-10)

early treatment 87 verbal Oral Reading Fluency Test not eligible

20 (compared to rct both arms the same); -17 (compared to randomization consent withheld)

<0.05

delayed treatment

97

randomization consent withheld

63

not eligible for randomization

81

grade 5 (10-11)

early treatment 54 verbal Oral Reading Fluency Test delayed/not eligible

NS

delayed treatment

51

randomization consent withheld

29

not eligible for randomization

115

grade 6 (11)

early treatment 12 verbal Oral Reading Fluency Test early/not eligible

NS

delayed treatment

9

randomization consent withheld

5

not eligible for randomization

24

9-11 years

early treatment 194 cognitive Woodcock-Johnson III Tests of Achievement, Standard Battery -- spelling subtest

not eligible

5 (compared to early/randomization withheld); -4 (compared to late)

<0.05

G-10

Study author, years

PMIDs Age Interventions No. analyzed

Outcome type

Outcome Favors If significant, net difference or OR (95%CI)

P between groups NS = not significant at alpha = 0.05

delayed treatment

196

randomization consent withheld

127

not eligible for randomization

223

9-11 years

early treatment 192 cognitive Woodcock-Johnson III Tests of Achievement, Standard Battery -- writing samples subtest

delayed/not eligible

NS

delayed treatment

195

randomization consent withheld

125

not eligible for randomization

223

9-11 years

early treatment 194 cognitive Woodcock-Johnson III Tests of Achievement, Standard Battery -- calculation subtest

not eligible

NS

delayed treatment

195

randomization consent withheld

127

not eligible for randomization

223

9-11 years

early treatment 195 verbal Comprehensive Test of Phonologial Processing - Elision subtest

delayed/not eligible

NS

delayed treatment

196

randomization consent withheld

127

not eligible for randomization

223

9-11 years

early treatment 195 verbal Comprehensive Test of Phonologial Processing - Rapid Letter Naming subtest

delayed/not eligible

NS

delayed treatment

196

randomization consent withheld

127

G-11

Study author, years

PMIDs Age Interventions No. analyzed

Outcome type

Outcome Favors If significant, net difference or OR (95%CI)

P between groups NS = not significant at alpha = 0.05

not eligible for randomization

223

9-11 years

early treatment 195 verbal Children's Version of the Hearing in Noise Test - competing noise from the front

early NS

delayed treatment

196

randomization consent withheld

127

not eligible for randomization

223

9-11 years

early treatment 195 verbal Children's Version of the Hearing in Noise Test - competing noise from the right

randomization consent witheld

1.4 (compared to not eligible)

<0.05

delayed treatment

196

randomization consent withheld

127

not eligible for randomization

223

9-11 years

early treatment 195 verbal Children's Version of the Hearing in Noise Test - competing noise from the left

early 0.8 (compared to not eligible)

<0.05

delayed treatment

196

randomization consent withheld

127

not eligible for randomization

223

9-11 years

early treatment 194 Behavior Disruptive Behavior Disorders Rating Scale - inattention factor

early NS

delayed treatment

196

randomization consent withheld

126

not eligible for randomization

223

9-11 years

early treatment 194 Behavior Disruptive Behavior Disorders Rating Scale - impulsitivity and

early 0.20 (compared to not eligible)

<0.05

G-12

Study author, years

PMIDs Age Interventions No. analyzed

Outcome type

Outcome Favors If significant, net difference or OR (95%CI)

P between groups NS = not significant at alpha = 0.05

overactivity factor delayed

treatment 196

randomization consent withheld

126

not eligible for randomization

223

9-11 years

early treatment 194 Behavior Disruptive Behavior Disorders Rating Scale - oppositional defiant factor

early/randomization withheld NS

delayed treatment

196

randomization consent withheld

126

not eligible for randomization

223

9-11 years

early treatment 194 cognitive Impairment Rating Scales - Overall functioning

early 0.18 (compared to not eligible)

<0.05

delayed treatment

196

randomization consent withheld

127

not eligible for randomization

223

9-11 years

early treatment 194 Behavior Social Skills Rating System delayed/not eligible

NS

delayed treatment

194

randomization consent withheld

126

not eligible for randomization

223

9-11 years

early treatment 195 cognitive Visual Continuous Performance Test - Inattention

early/randomization withheld NS

delayed treatment

196

randomization consent withheld

127

not eligible for randomization

223

G-13

Study author, years

PMIDs Age Interventions No. analyzed

Outcome type

Outcome Favors If significant, net difference or OR (95%CI)

P between groups NS = not significant at alpha = 0.05

9-11 years

early treatment 195 cognitive Visual Continuous Performance Test - Impulsivity

early/randomization withheld NS

delayed treatment

196

randomization consent withheld

127

not eligible for randomization

223

9-11 years

early treatment 155 verbal Auditory Continuous Performance Test - Inattention

delayed/randomization withheld

NS

delayed treatment

153

randomization consent withheld

100

not eligible for randomization

128

9-11 years

early treatment 155 verbal Auditory Continuous Performance Test - Inattention

delayed NS

delayed treatment

153

randomization consent withheld

100

not eligible for randomization

128

Rach 1991 2070526 ND TT 22 verbal verbal comprehension score TT NS control 21 TT 21 verbal verbal expression score TT NS control 20 Schilder 1997

9372253 2-4 years

TT 13 verbal language measures: word forms production

TT 26.4 (SD 0.92) P=0.03

control 14 2-4

years TT 13 verbal language measures: concealed

meaning TT NS

control 14 2-4

years TT 13 verbal language measures: phonemic

segmentation TT NS

G-14

Study author, years

PMIDs Age Interventions No. analyzed

Outcome type

Outcome Favors If significant, net difference or OR (95%CI)

P between groups NS = not significant at alpha = 0.05

control 14 2-4

years TT 13 verbal language measures: sound

blending control NS

control 14 2-4

years TT 13 verbal language measures: auditory

discrimination TT 0.08 (SD 0.03) P=0.03

control 14 Rovers 2000 10969126 0.5

years TT 93 verbal Reynell test (comprehensive

language development) watchful waiting

NS

watchful waiting 94 1 year TT 93 verbal Reynell test (comprehensive

language development) TT NS

watchful waiting 94 0.5

years TT 93 verbal Schlichting test (expressive

language development) watchful waiting

NS

watchful waiting 94 1 year TT 93 verbal Schlichting test (expressive

language development) watchful waiting

NS

watchful waiting 94 Peters 1994 8195687 93

months TT 37 verbal Grapheme (%) TT NS

Control 151 93

months TT 37 cognitive Spelling: Words (%) TT NS

Control 151 93

months TT 37 cognitive Spelling: Pseudowords (%) TT NS

Control 151 93

months TT 37 cognitive One-Minute (# correct) TT NS

Control 151 93

months TT 37 cognitive Sentence Verification: Correct

sentences (msec) TT NS

Control 151 93

months TT 37 cognitive Sentence Verification: Incorrect

sentences (msec) TT NS

Control 151

G-15

Study author, years

PMIDs Age Interventions No. analyzed

Outcome type

Outcome Favors If significant, net difference or OR (95%CI)

P between groups NS = not significant at alpha = 0.05

93 months

TT 37 cognitive Sentence Verification: Correct sentences (%)

TT NS

Control 151 93

months TT 37 cognitive Sentence Verification: Incorrect

sentences (%) TT NS

Control 151 93

months TT 37 cognitive Teachers' Ratings: Writing 1 TT <0.001

Control 151 93

months TT 37 cognitive Teachers' Ratings: Writing 2 Control NS

Control 151 93

months TT 37 cognitive Teachers' Ratings: Reading 3 TT NS

Control 151 93

months TT 37 cognitive Teachers' Ratings: Reading 4 neither NS

Control 151 93

months TT 37 cognitive Teachers' Ratings: Reading 5 Control NS

Control 151 93

months TT 37 cognitive Teachers' Ratings: Arithmetic 6 Control NS

Control 151 93

months TT 37 cognitive Teachers' Ratings: Arithmetic 7 Control NS

Control 151 93

months TT 37 cognitive Teachers' Ratings: Arithmetic 8 neither NS

Control 151 93

months TT 37 verbal Word Recognition: Words (msec) TT NS

Control 151 93

months TT 37 verbal Word Recognition: Pseudowords

(msec) TT NS

Control 151 93

months TT 37 verbal Word Recognition: Words (%) TT NS

G-16

Study author, years

PMIDs Age Interventions No. analyzed

Outcome type

Outcome Favors If significant, net difference or OR (95%CI)

P between groups NS = not significant at alpha = 0.05

Control 151 93

months TT 37 verbal Word Recognition: Pseudowords

(%) Control NS

Control 151 Grievink 1993

8246466 93 months

TT 132 verbal Word Forms Production neither NS

Control 51 93

months TT 132 cognitive Concealed Meaning Control NS

Control 51 93

months TT 132 verbal Phonemic Segmentation: Words Control NS

Control 51 93

months TT 132 verbal Phonemic Segmentation: Pseudo Control NS

Control 51 93

months TT 132 verbal Sound Blending: Words TT NS

Control 51 93

months TT 132 verbal Sound Blending: Pseudo Control NS

Control 51 93

months TT 132 verbal Auditory Discrimination of Unequal

Pairs: Words Control NS

Control 51 93

months TT 132 verbal Auditory Discrimination of Unequal

Pairs: Pseudo Control NS

Control 51 93

months TT 132 verbal Auditory Discrimination of Equal

Pairs: Words TT NS

Control 51 93

months TT 132 verbal Auditory Discrimination of Equal

Pairs: Pseudo TT NS

Control 51 Hall 2009 19260880 4.5

years Early surgery 76 cognitive School entry: Language Early

surgery OR: 3.45 (1.42, 8.39)

0.006

Watchful waiting 60

G-17

Study author, years

PMIDs Age Interventions No. analyzed

Outcome type

Outcome Favors If significant, net difference or OR (95%CI)

P between groups NS = not significant at alpha = 0.05

4.5 years

Early surgery 76 cognitive School entry: Reading Watchful waiting

NS (0.510)

Watchful waiting 60 4.5

years Early surgery 76 cognitive School entry: Writing Early

surgery OR: 3.74 (1.51, 9.27)

0.004

Watchful waiting 60 4.5

years Early surgery 76 cognitive School entry: Mathematics Early

surgery NS (0.197)

Watchful waiting 60 7-8

years Early surgery 27 Behavior Behaviour - teacher report:

Prosocial Early surgery

NS (0.877)

Watchful waiting 24 7-8

years Early surgery 27 Behavior Behaviour - teacher report:

Hyperactivity Early surgery

NS (0.363)

Watchful waiting 24 7-8

years Early surgery 27 Behavior Behaviour - teacher report:

Emotional problems Early surgery

OR: 4.11 (1.15, 14.64)

0.029

Watchful waiting 24 7-8

years Early surgery 27 Behavior Behaviour - teacher report:

Conduct problems Watchful waiting

NS (0.803)

Watchful waiting 24 7-8

years Early surgery 27 Behavior Behaviour - teacher report: Peer

problems Early surgery

NS (0.816)

Watchful waiting 24 7-8

years Early surgery 27 Behavior Behaviour - teacher report: Total

score Early surgery

NS (0.237)

Watchful waiting 24 7-8

years Early surgery 35 verbal Speech/language: Comprehension Early

surgery NS (0.366)

Watchful waiting 33 7-8

years Early surgery 34 verbal Speech/language: Oral expression Early

surgery NS (0.143)

Watchful waiting 32 7-8

years Early surgery 35 verbal Speech/language: Non-word: 3

syllable Early surgery

NS (0.773)

Watchful waiting 32 7-8

years Early surgery 35 verbal Speech/language: Non-word: 4

syllable Early surgery

NS (0.656)

G-18

Study author, years

PMIDs Age Interventions No. analyzed

Outcome type

Outcome Favors If significant, net difference or OR (95%CI)

P between groups NS = not significant at alpha = 0.05

Watchful waiting 32 7-8

years Early surgery 35 verbal Speech/language: Non-word: 5

syllable Early surgery

NS (0.101)

Watchful waiting 32 7-8

years Early surgery 35 verbal Speech/language: Non-word: total Early

surgery NS (0.288)

Watchful waiting 32 7-8

years Early surgery 36 cognitive IQ: Verbal IQ Early

surgery NS (0.265)

Watchful waiting 30 7-8

years Early surgery 32 cognitive IQ: Performance IQ Early

surgery NS (0.145)

Watchful waiting 30 7-8

years Early surgery 29 cognitive IQ: Total IQ Early

surgery NS (0.100)

Watchful waiting 29 7-8

years Early surgery 81 cognitive SATS KS1: Reading overall Early

surgery NS (0.258)

Watchful waiting 64 7-8

years Early surgery 81 cognitive SATS KS1: Writing Early

surgery NS (0.192)

Watchful waiting 64 7-8

years Early surgery 81 cognitive SATS KS1: Mathematics Early

surgery NS (0.079)

Watchful waiting 64 Maw 1999 10459904 18

months TT (Tympanostomy tubes within 6 weeks)

75 verbal Verbal comprehension: standardized score

TT NS (0.14)

Watchful waiting (for 9 months then tubes if needed)

67

18 months

TT (Tympanostomy tubes within 6 weeks)

75 verbal Expressive language: standardized score

TT NS (0.059)

Watchful waiting 67

G-19

Study author, years

PMIDs Age Interventions No. analyzed

Outcome type

Outcome Favors If significant, net difference or OR (95%CI)

P between groups NS = not significant at alpha = 0.05

(for 9 months then tubes if needed)

18 months

TT (Tympanostomy tubes within 6 weeks)

75 verbal Verbal comprehension: chronological age/equivalent age

TT NS (0.36)

Watchful waiting (for 9 months then tubes if needed)

67

18 months

TT (Tympanostomy tubes within 6 weeks)

75 verbal Expressive language: chronological age/equivalent age

TT NS (0.36)

Watchful waiting (for 9 months then tubes if needed)

67

18 months

TT (Tympanostomy tubes within 6 weeks)

75 Behavior Richman score >= 10 TT NS (0.66)

Watchful waiting (for 9 months then tubes if needed)

67

18 months

TT (Tympanostomy tubes within 6 weeks)

75 Behavior Richman score TT NS (0.13)

Watchful waiting (for 9 months then tubes if needed)

67

Vlastos 2011 21205368 1 year TT AND adenoidectomy

22 QOL OM-6 Myringotomy AND adenoidectomy

NS

Myringotomy 23

G-20

Study author, years

PMIDs Age Interventions No. analyzed

Outcome type

Outcome Favors If significant, net difference or OR (95%CI)

P between groups NS = not significant at alpha = 0.05

AND adenoidectomy

G-21

Appendix H. Harms

Table H1. Evidence map of studies reporting adverse events

Aut

hor P

MID

Cou

ntry

Des

ign

(Rec

ruitm

ent p

erio

d)

Tube

Typ

e [a

rm d

escr

iptio

n]

Perio

pera

tive

Com

plic

atio

ns

Oto

rrhe

a Tu

be B

lock

age

Gra

nula

tion

Tiss

ue

Prem

atur

e Ex

trus

ion

TT D

ispl

acem

ent

Pers

iste

nt P

erfo

ratio

n M

yrin

gosc

lero

sis

Atr

ophy

|Ate

lect

asis

|Ret

ract

ion

C

hole

steo

tom

a H

earin

g Lo

ss

Ah-Tye 11389239 US prosp cohort (1992-1996) Teflon, Armstrong-type tube X

Ahmet 11271428 Turkey prosp cohort (1988-1997)

Paparella type-1, type-2, Shepard Grommet or Modified T tympanostomy tubes X

Allen 16156910 US prosp cohort (9/2001-11/2001) Sheehy (0.12 cm diameter) tube X

Baarle 1169745 Netherlands prosp cohort Double-flanged, Silastic tubes (Richards) X X

Barfoed 7190819 Denmark prosp cohort (nr) nr X X X X

Bernard 1991 1861917 Canada prosp rct (nr) Reuter bobbin, Richart "T" X X X X

Birck 1267356 US prosp cohort (1972-1974) nr X X X X X X

Bonding 4215997 US cohort (1967-1969) nr X X

Bonding 4702615 Denmark cohort grommets X

Brodsky 10591365 US prosp cohort (1998-1999) nr X X X

Brown 8231117 US cohort Goode T-tubes X X X X Cannon 11797262 US nrcs Ultracil tube X

H-1

Aut

hor P

MID

Cou

ntry

Des

ign

(Rec

ruitm

ent p

erio

d)

Tube

Typ

e [a

rm d

escr

iptio

n]

Perio

pera

tive

Com

plic

atio

ns

Oto

rrhe

a Tu

be B

lock

age

Gra

nula

tion

Tiss

ue

Prem

atur

e Ex

trus

ion

TT D

ispl

acem

ent

Pers

iste

nt P

erfo

ratio

n M

yrin

gosc

lero

sis

Atr

ophy

|Ate

lect

asis

|Ret

ract

ion

C

hole

steo

tom

a H

earin

g Lo

ss

Cannon 11797262 US nrcs Silastic tubes X Carignan 17049144 Canada

prosp cohort (2003-2004) Goode T-tubes X

Casselbrant 1565551 US prosp rct (1981-1988) Teflon Armstrong-type TT X

Costa 3472336 Brazil prosp cohort nr X X

Daly 12759263 US prosp cohort (1987-1990) nr X X X X X

Daly 9738746 US cross-sectional (1979-1985) [adolescents and young adults treated with TT] X X

Daly 9738746 US cross-sectional (1985-1990) [children treated with TT] X X X

De Beer 15224825 Netherlands

prosp cohort (1982-1983) nr X X

De Beer 16151352 Netherlands prosp ncrs [positive history of otitis media and ventilation tube insertion] X X X

Debruyne 3177616 Belgium prosp cohort nr X X

Debruyne 3799183 Belgium cohort nr X X

Debruyne 8336923 Belgium prosp cohort (nr) Sheppard tube X

Djurhuus 25724629 Denmark

retro cohort (1997-2011) nr X

Djurhuus 25724629 Denmark

retro cohort (1997-2011) various [data from National Registers X

Dohar 16880248 US prosp rct (2003-2004) [underwent tympanostomy] X

Eliachar 6613541 Israel prosp cohort (1975-1981) Goode long-term T-shaped silicone design tubes X X X X X X

Fiebach 3570884 prosp cohort nr X X X

H-2

Aut

hor P

MID

Cou

ntry

Des

ign

(Rec

ruitm

ent p

erio

d)

Tube

Typ

e [a

rm d

escr

iptio

n]

Perio

pera

tive

Com

plic

atio

ns

Oto

rrhe

a Tu

be B

lock

age

Gra

nula

tion

Tiss

ue

Prem

atur

e Ex

trus

ion

TT D

ispl

acem

ent

Pers

iste

nt P

erfo

ratio

n M

yrin

gosc

lero

sis

Atr

ophy

|Ate

lect

asis

|Ret

ract

ion

C

hole

steo

tom

a H

earin

g Lo

ss

Germany (1979-1984)

Fior 6526581 Italy prosp cohort (1968-1978) Shepard type X X X

Florentzson 22648089 Sweden

prosp cohort (1/1996-12/1996)

Tympovent 0.9 mm diameter straight fluoroplastic tube from Atos Medical X

Friedman 11551611 US prosp cohort nr X Gates 2492178 US prosp rct Shepard-type X Gates 2492178 US prosp rct Shepard-type [adenoidectomy + TT] X

Gates 3128752 US prosp cohort (1980-1986)

Shepard-type tube (1.1 mm inner diameter)[TT & Adenoidectomy] X

Gates 3128752 US prosp cohort (1980-1986) Shepard-type tube (1.1 mm inner diameter)[TT] X

Gates 3683478 US prosp rct (1980-1984) Shepherd tubes [TT and TT+ adenoidectomy arms] X X X X

Golz 10187945 US, Israel retro cohort (1980-1994) 93% standard polyethylene tubes, 7% Goode T tubes X X

Golz 10406312 Israel retro cohort (1978-1997)

"homemade" polyethylene tubes in 5143 ears, Goode T-tubes in 432 ears X

Gourin 10208683 US prosp cohort (1995-1997) Silver oxide-impregnated Sheehy-type tympanostomy tubes X

Gundersen 1267702 Norway prosp cohort polyethylene ventilating tube X X X

Håkansson 25554572 Sweden

prosp cohort (1996-2006) nr [TT]

Hammaren-Malmi 17582514 Finland

prosp cohort (2001-2002) nr X

Hampton 9118580 Ireland prosp cohort Armstrong ventilation tubes X

Heaton 8877228 UK prosp cohort (1986-1988) nr X X X

Hoffman 12220208 US prosp/retro cohort nr X

H-3

Aut

hor P

MID

Cou

ntry

Des

ign

(Rec

ruitm

ent p

erio

d)

Tube

Typ

e [a

rm d

escr

iptio

n]

Perio

pera

tive

Com

plic

atio

ns

Oto

rrhe

a Tu

be B

lock

age

Gra

nula

tion

Tiss

ue

Prem

atur

e Ex

trus

ion

TT D

ispl

acem

ent

Pers

iste

nt P

erfo

ratio

n M

yrin

gosc

lero

sis

Atr

ophy

|Ate

lect

asis

|Ret

ract

ion

C

hole

steo

tom

a H

earin

g Lo

ss

Hormann -Iowa-Kollectiv 1816937 Germany prosp nrcs [cleft palate - University of Hamburg] X X X X

Hormann -Iowa-Kollectiv 1816937 Germany prosp nrcs [cleft palate - University of Hamburg] X X

Ida 19324425 US prosp cohort pressure equalization tube X X Ingels 16429748 Netherlands

prosp rct (1996-1997) Bevel Bobbins, Entermed BV, The Netherlands [TT] X

Isaacson 18722211 US prosp cohort (1997-2007) Armstrong beveled grommet tube X X X

Jamal 7543180 Saudi Arabia prosp ncrs [TT] X

Jamal 7543180 Saudi Arabia prosp ncrs [TT + xylometazoline hydrochloride] X

Jung 19715725 Korea cohort (2004-2008) nr X

Khan 16773972 Pakistan prosp cohort (2001-2003) nr X X X

Kinnari 20122337 Finland prosp rct (2001-2002) Xomed Soileau Tytan X X X X X X X

Kokko 1267359 Finland cohort (1965-1971) nr X X X X

Kujala 22466327 Finland prosp rct (2002-2004) Donaldson silicone tubes X

Levine 8179266 US prosp cohort Donaldson, Shephard, Paparella or Reuter/bobbin X Levinson 6819525 US prosp cohort X X

Li 10547462 US prosp cohort (1987-1991) Donaldson tubes, Reuter Bobbin tubes, Shepard tubes or other X

Luo 25465449 China prosp nrcs (2011-2012) [tympanostomy tube insertion] X X X X X

Mackenzie 6541254 UK prosp cohort (1978-1980)

Pappas 1974, Shah 1971 (Exmoor 142, Shepard 137, Bobbin 132, Arrow 58, Shah 131, Armstrong 138, Colar Button 141, X X X X X

H-4

Aut

hor P

MID

Cou

ntry

Des

ign

(Rec

ruitm

ent p

erio

d)

Tube

Typ

e [a

rm d

escr

iptio

n]

Perio

pera

tive

Com

plic

atio

ns

Oto

rrhe

a Tu

be B

lock

age

Gra

nula

tion

Tiss

ue

Prem

atur

e Ex

trus

ion

TT D

ispl

acem

ent

Pers

iste

nt P

erfo

ratio

n M

yrin

gosc

lero

sis

Atr

ophy

|Ate

lect

asis

|Ret

ract

ion

C

hole

steo

tom

a H

earin

g Lo

ss

Paparella 60)

MacKinnon 4105168 UK prosp cohort (1965-1971) nr X X X

Mandel 2789777 US prosp rct (1979-1984) Teflon Armstrong-type TT X

Mandel 8085732 US prosp cohort (1979-1990) Teflon Armstrong-type X

Marzouk 22183900 US prosp cohort (2009-2010) nr X

Maw 10459904 UK prosp rct [TT after 9 months of watchful waiting] Maw 10459904 UK prosp rct [TT within 6 weeks] Moore 2396808 Australia cohort collar-button or Shephard Muenker 6778334 Germany

prosp cohort (1966-1978) nr X X X X

O'Niel 26115935 US prosp cohort (2009-nr) various, including Sheehy, Armstrong, T tube, Activent X X X

O’Reilly 18594333 US prosp cohort nr X Owen 8436453 US prosp cohort Armstrong bevelled tube X X

Paradise 11309632 US prosp rct (1991-1995)

Armstrong [TT late treatment; underwent TT insertion 6-9 months after initiaition of symptoms] X X X X

Paradise 11309632 US prosp rct (1991-1995)

Armstrong [TT early treatment; underwent TT insertion at initiaition of symptoms] X X X X

Paradise 2181158 US prosp rct/nrcs (1971-1985) [TT]

Paradise 2181158 US prosp rct/nrcs (1971-1985) [TT & Adenoidectomy] X X

Pereira 16446953 Brazil prosp cohort (2001-2002)

Short-term ventilation tubes, made of silicone, measuring 1.2 x 2.6 mm, type Donaldson X X X X X

Plotkin 7195446 US prosp cohort (1977-1979)

Castelli membrane, Donaldson design, silicone tube (Xomed XO-1201) X X X

Poetker 17178938 US prosp rct (2002- Teflon-coated, fluoroplastic Armstrong beveled TT [receiving X

H-5

Aut

hor P

MID

Cou

ntry

Des

ign

(Rec

ruitm

ent p

erio

d)

Tube

Typ

e [a

rm d

escr

iptio

n]

Perio

pera

tive

Com

plic

atio

ns

Oto

rrhe

a Tu

be B

lock

age

Gra

nula

tion

Tiss

ue

Prem

atur

e Ex

trus

ion

TT D

ispl

acem

ent

Pers

iste

nt P

erfo

ratio

n M

yrin

gosc

lero

sis

Atr

ophy

|Ate

lect

asis

|Ret

ract

ion

C

hole

steo

tom

a H

earin

g Lo

ss

2003) ofloxacin otic drops]

Poetker 17178938 US prosp rct (2002-2003)

Teflon-coated, fluoroplastic Armstrong beveled TT [no postoperative otic drop prophylaxis] X

Poetker 17178938 US prosp rct (2002-2003)

Teflon-coated, fluoroplastic Armstrong beveled TT [receiving neomycin sulfate-polymyxin B sufate-hydrocortisone otic drops] X

Postma 9350484 US prosp cohort (1988-1991) Amstrong grommt or straight Armstrong X

Powell 25598389 UK prosp cohort (2004-2005) nr X X X X X

Praveen 15992470 UK prosp cohort (1998-2003) Shah ventilation tubes X X

Rakover 9176804 Israel nrcs T tube, Paparella TT [TT: no ear drops] X

Rakover 9176804 Israel nrcs T tube, Paparella TT [TT with ear drops (preventive dexamethasone, neomycin and polymxin B)] X

Roland 14702493 US, Canada prosp rct nr X

Roos 2128487 Sweden prosp cohort polyethylene X

Rosenfeld 10807325 US prosp cohort (1997-1998)

short-acting grommet-type tubes, designed to extrude spontaneously within 6-18 months X

Rothera 4040147 UK prosp cohort (1980-1982)

Xomed silicone Goode T-Tubes (1.1 mm. internal diameter, 12 mm. length) X X X

Saki 24303379 Iran prosp cohort (2009-2011) nr X X X X X X X X

Siddiqui 9225174 UK prosp cohort (1987-1992) Mangat tube (Xomed) X X

Siegel 12161732 US prosp nrcs (1998-2000)

Reuter bobbin tubes [underwent Laser Office Ventilation of Ears with Insertion of Tubes (LOVE IT)] X

Siegel 12161732 US prosp nrcs (1998-2000)

Reuter bobbin tubes [underwent standard cold surgical myringotomy and tube placement (M&T)] X

Slack 6470572 UK prosp cohort Shepard grommet X Smillie 25171763 nrcs (2002-2012) [cleft lip palate; underwent VT insertion] X X X X X X X

H-6

Aut

hor P

MID

Cou

ntry

Des

ign

(Rec

ruitm

ent p

erio

d)

Tube

Typ

e [a

rm d

escr

iptio

n]

Perio

pera

tive

Com

plic

atio

ns

Oto

rrhe

a Tu

be B

lock

age

Gra

nula

tion

Tiss

ue

Prem

atur

e Ex

trus

ion

TT D

ispl

acem

ent

Pers

iste

nt P

erfo

ratio

n M

yrin

gosc

lero

sis

Atr

ophy

|Ate

lect

asis

|Ret

ract

ion

C

hole

steo

tom

a H

earin

g Lo

ss

Scotland Smillie 25171763 Scotland nrcs (2002-2012) [no cleft lip palate; underwent VT insertion] X X X X X X X

Spielmann 18047760 UK prosp cohort (2003-2004) nr [second cohort] X X X X

Spielmann 18047760 UK prosp cohort (2000-2000) nr [first cohort]

Spilsbury 23737350 Austalia

retro cohort (1980-2009) nr X

Suetake 2239252 Japan prosp cohort (1986-1987) nr X X

Tavin 3372141 US prosp cohort (1982-1985) various X X

Tos 3814387 Denmark prosp cohort (1970-1975) nr X X X

Tos 7192477 Denmark cohort Armstrong tube X Tos 985199 Denmark prosp cohort nr X X X X Tuli 23119801 India cohort nr X X X X Valtonen 10435125 Finland

prosp cohort (1983-1984) Shah vent Teflon tube, inner diameter 1.1 mm X X X X

Valtonen 12150521 Finland

prosp cohort (1983-1984) Shah vent Teflon tube, inner diameter 1.1 mm X X

Valtonen 16094135 Finland

prosp cohort (1983-1993) Shah vent Teflon tube (Xomed) X X X

Van Cauwenberge 576016 Belgium prosp cohort nr X

van Dongen 23874870 Netherlands

retro cohort (2009-2011) nr X

van Heerbeek 16510637 Netherlands

prosp rct (2000-2002) fluoroplastic, Bevel Bobbin-type TTs (TympVent)

van Heerbeek 16510637 prosp rct (2000- fluoroplastic, Bevel Bobbin-type TTs (TympVent) [pneumococcal

H-7

Aut

hor P

MID

Cou

ntry

Des

ign

(Rec

ruitm

ent p

erio

d)

Tube

Typ

e [a

rm d

escr

iptio

n]

Perio

pera

tive

Com

plic

atio

ns

Oto

rrhe

a Tu

be B

lock

age

Gra

nula

tion

Tiss

ue

Prem

atur

e Ex

trus

ion

TT D

ispl

acem

ent

Pers

iste

nt P

erfo

ratio

n M

yrin

gosc

lero

sis

Atr

ophy

|Ate

lect

asis

|Ret

ract

ion

C

hole

steo

tom

a H

earin

g Lo

ss

Netherlands 2002) vaccination]

Velepic 21397957 Croatia prosp rct (2004-2009) nr X X X

Walker 9287928 Australia prosp cohort Shepard grommet, Shah vent tube, Sheehy collar button vent tube X X X

Wallace 15533143 UK prosp rct (2001-2002) Shepard or T tube X X X

Weigel 2645490 US prosp cohort (1983-1984)

Goode T-tubes, Armstrong Teflon, Reuter-Bobbin Stainless Steel, Shepard Teflon X X X

H-8

Table H2. Perioperative complications Author PMID

Country

Design (recruitment

period) Tube Type [arm desc.]

Age (SD) [min, max]

% male

%rAOM [%COME] Followup N

[ears] % Perioperative Complications Definition

Brodsky 10591365 US

prosp cohort (1998-1999) nr

3.95 (5.09) [0.50, 23.67]

56.6 [75.8] 1 to 3 months 54 [96] [1.04%] ear canal abrasion

Hoffman 12220208 US

prosp/retro cohort nr nr nr nr nr 3198 0.81%

intraoperative, including upper airway obstruction, agitation, prolonged recovery, emesis, laryngospasm, desaturation, bradycardia, dysrhythmia, stridor

Isaacson 18722211 US

prosp cohort (1997-2007)

Armstrong beveled grommet tube

[0.11, 21.00] nr nr nr [10000] [0.01%] tympanic membrane tear

Kujala 22466327 Finland

prosp rct (2002-2004)

Donaldson silicone tubes 16.1(4.) 58 100[0] 1 year 200 0.00% Hemorrhage or anesthetic

complications

Table H3. Otorrhea Author PMID

Country Design

(recruitment period)

Tube Type [arm desc.]

Age (SD) [min, max]

% male

%rAOM [%COME] Followup N [ears] %

Otorrhea Definition

Ah-Tye 11389239 US

prosp cohort (1992-1996)

Teflon, Armstrong-type tube

1.37 [0.50, 3.00]

59.5 nr 24 months 173 58.61% nr

Bernard 1991 1861917 Canada

prosp rct (nr) Reuter bobbin, Richart "T" 4.7 56.7 nr 18 months 60 13.30% nr

Brodsky 10591365 US

prosp cohort (1998-1999) nr

3.95 (5.09) [0.50, 23.67]

56.6 [75.8] 1 to 3 months 54 [96] 11.11% nr

Brown 8231117 US cohort Goode T-tubes nr nr nr 6 months 168 [328] 52.38% infections

Debruyne 3177616 Belgium

prosp cohort nr 4.92 nr 45.2% [54.8]

until extrusion

906 [1685]

14.79% [10.45%] nr

H-9

Author PMID Country

Design (recruitment

period) Tube Type [arm

desc.] Age (SD)

[min, max]

% male

%rAOM [%COME] Followup N [ears] %

Otorrhea Definition

Debruyne 3799183 Belgium

cohort nr 2.70+ 55.4 nr 0.5 to 6 years

906 [1685]

14.90% [10.45%] nr

Debruyne 8336923 Belgium

prosp cohort (nr) Sheppard tube nr 58 100% 1 year 126 10.00% 3 or more episodes

Gates 2492178 US prosp rct Shepard-type [4.00,

8.00] 58 nr 2 years 129 28.68% purulent otorrhea >=1 episode

Gates 3128752 US

prosp cohort (1980-1986)

Shepard-type tube (1.1 mm inner diameter)[TT & Adenoidectomy]

[4.00, 8.00] 60.3 nr nr 155 32.26%

purulent liquid was unequivocably present in external auditory canal, regardless of whether a tube was present or not, not ocunting dried secretions or blood clots

Gates 3128752 US

prosp cohort (1980-1986)

Shepard-type tube (1.1 mm inner diameter)[TT]

[4.00, 8.00] 60.3 nr nr 227 22.47%

purulent liquid was unequivocably present in external auditory canal, regardless of whether a tube was present or not, not ocunting dried secretions or blood clots

Golz 10187945 US, Israel

retro cohort (1980-1994)

93% standard polyethylene tubes, 7% Goode T tubes

4.20 (1.40) [0.83, 10.00]

55 91 [7.5]

at least 1 year after extrusion or removal

1360 [2604] 10.45% 3 or more episodes

Heaton 8877228 UK

prosp cohort (1986-1988) nr

5.00 [1.00, 12.00]

60.6 0 [100] nr 127 14.17% discharge via one or both of their tubes

Hörmann 1816937 Germany

prosp nrcs [cleft palate - University of Hamburg]

7.43 [5.00, 10.00]

nr nr 8 years 126 [252] 10.32% chronic recurring OME

through tubes Ida 19324425 US

prosp cohort pressure equalization tube

[0.67, 4.00] nr 0 [100] 16 months 50 4.00% nr

Ingels 16429748 Netherlands

prosp rct (1996-1997)

Bevel Bobbins, Entermed BV, The Netherlands [TT]

0.14 (0.01) 58.8 0 [100] 1 year 93 82.80% nr

H-10

Author PMID Country

Design (recruitment

period) Tube Type [arm

desc.] Age (SD)

[min, max]

% male

%rAOM [%COME] Followup N [ears] %

Otorrhea Definition

Jung 19715725 Korea

cohort (2004-2008) nr

4.50 (2.20) [2.00, 7.00]

65.7 0 [100] 6 to 24 months 289 23.18%

active otorrhea from middle ear cavity through tympanostomy tube

Kinnari 20122337 Finland

prosp rct (2001-2002)

Xomed Soileau Tytan

4.1[0.5, 15] 61 36[64]

until extrusion or removal

170[298] [6.7%] chronic otorrhea

Levinson 6819525 US prosp cohort [1.00,

11.00+] nr nr 5 months 64 [124] [1.61%] acute otitis media

Luo 25465449 China

prosp nrcs (2011-2012)

[tympanostomy tube insertion]

4.80 (1.00) [2.00, 8.00]

50.9 nr 2 years 55 32.73% otorrhea

Mandel 8085732 US

prosp cohort (1979-1990)

Teflon Armstrong-type

3.60 [0.50, 12.00]

nr nr nr 246 50.00% nr

Marzouk 22183900 US

prosp cohort (2009-2010) nr

3.60 (1.80) [0.90, 9.00]

67.1 15.8 [51.3] 1 year 79 34.18% nr

O’Reilly 18594333 US

prosp cohort nr 2.70 (2.40) [0.25, 17.00]

55.2 nr 6 months 509 70.33% nr

Owen 8436453 US prosp cohort Armstrong bevelled

tube 2.08 [0.42, 4.00]

nr nr 6 months 52 [98] [28.21%] nr

Pereira 16446953 Brazil

prosp cohort (2001-2002)

Short-term ventilation tubes, made of silicone, measuring 1.2 x 2.6 mm, type Donaldson

2.89 (1.54) [0.92, 9.33]

60 69.3 [30.7] 38 months 75 [150] 61.64% otorrhea at some time

Plotkin prosp cohort Castelli membrane, 5.20 60.7 0 [100] nr 89 [162] 12.36% purulent otitis media

H-11

Author PMID Country

Design (recruitment

period) Tube Type [arm

desc.] Age (SD)

[min, max]

% male

%rAOM [%COME] Followup N [ears] %

Otorrhea Definition

7195446 US (1977-1979) Donaldson design, silicone tube (Xomed XO-1201)

[2.50, 11.00]

and serous otitis media

Powell 25598389 UK

prosp cohort (2004-2005) nr 4.60 nr nr 9 weeks to

10 years 89 19.10% otorrhea at 9 weeks

Rosenfeld 10807325 US

prosp cohort (1997-1998)

short-acting grommet-type tubes, designed to extrude spontaneously within 6-18 months

med 1.40 [0.50, 9.90]

60 56 [42] 2 to 4 months 248 29.91% at first postoperative

office visit

Rothera 4040147 UK

prosp cohort (1980-1982)

Xomed silicone Goode T-Tubes (1.1 mm. internal diameter, 12 mm. length)

nr nr 0 [100] 30 months 73 [131] 20.55% nr

Saki 24303379 Iran

prosp cohort (2009-2011) nr [0.83,

6.00] 55.8 0 [100] 12 to 18 months 208 17.79%

transient otorrhea; delayed otorrhea; chronic otorrhea non-responsive to medical treatment

Siddiqui 9225174 UK

prosp cohort (1987-1992)

Mangat tube (Xomed)

mode 5.00 [0.50, 14.00]

61.8 0 [100] 3 years 191 [322]

13.09% [11.18%]

had ear discharge on one or more occasions, requiring abx and eardrops

Smillie 25171763 Scotland

nrcs (2002-2012)

[no cleft lip palate; underwent VT insertion]

med 3.50 [0.60, 10.40]

55 nr nr 60 60.00% nr

Spielmann 18047760 UK

prosp cohort (2003-2004) nr [second cohort]

5.30 [0.83, 9.00]

61.4 18.8 [81.2] 3 months 84 [195] 14.29% nr

Suetake prosp cohort nr 6.20 59.6 0 [100] nr 52 [90] 47.27% recurrence of SOM

H-12

Author PMID Country

Design (recruitment

period) Tube Type [arm

desc.] Age (SD)

[min, max]

% male

%rAOM [%COME] Followup N [ears] %

Otorrhea Definition

2239252 Japan

(1986-1987) (2.00) [3.00, 11.00]

Tavin 3372141 US

prosp cohort (1982-1985) various

4.80 (1.50) [0.33, 16.00]

63.2 nr 365 to 728 days 95 [187] [9.09%] excluding post

operative otorrhea

Tuli 23119801 India

cohort nr nr 66.7 0 [100] nr 100 12.00% excessive bleeding

Valtonen 10435125 Finland

prosp cohort (1983-1984)

Shah vent Teflon tube, inner diameter 1.1 mm

0.84 [0.42, 1.33]

58.4 34.2 [65.8] 5 years 281

[281] [66.55%] post-tympanostomy otorrhea during primary ventilation tube

Valtonen 16094135 Finland

prosp cohort (1983-1993)

Shah vent Teflon tube (Xomed) nr 51.4 0 [100] 5 to 7.2

years 72 [124] 6.94% ongoing OME

van Dongen 23874870 Netherlands

retro cohort (2009-2011) nr 4.40

(2.30) 58 nr nr 1184 67.00% one or more episodes in first year after TT placement

Weigel 2645490 US

prosp cohort (1983-1984)

Goode T-tubes, Armstrong Teflon, Reuter-Bobbin Stainless Steel, Shepard Teflon

3.80 [0.60, 13.00]

59 45 [41] 21 months 75 [150] [35.33%] nr

Table H4. Tube blockage Author PMID

Country Design

(recruitment period)

Tube Type [arm desc.] Age (SD)

[min, max]

% male

%rAOM [%COME] Followup N [ears] % Tube

Blockage Defintion

Allen 16156910 US

prosp cohort (9/2001-11/2001)

Sheehy (0.12 cm diameter) tube 4 [0.75, 11.83] 68.1 74 [19.5] 2 weeks 112 10.71% nr

Birck 1267356 US

prosp cohort (1972-1974) nr nr 59.2 nr 6+ months 736

[2327] [2.49%] tubes occluded

H-13

Author PMID Country

Design (recruitment

period) Tube Type [arm desc.]

Age (SD) [min, max]

% male

%rAOM [%COME] Followup N [ears] % Tube

Blockage Defintion

Brodsky 10591365 US

prosp cohort (1998-1999) nr

3.95 (5.09) [0.50, 23.67]

56.6 [75.8] 1 to 3 months 54 [96] [4.05%] nr

Dohar 16880248 US

prosp rct (2003-2004) [underwent tympanostomy] [0.50,

11.00] 52.5 nr 3 weeks 39 2.56% device blockage

Eliachar 6613541 Israel

prosp cohort (1975-1981)

Goode long-term T-shaped silicone design tubes

8.33 [4.50, 16.00]

nr nr 8 to 72 months

122 [203] [2.96%] blockage

Isaacson 18722211 US

prosp cohort (1997-2007)

Armstrong beveled grommet tube

[0.11, 21.00] nr nr nr [10000] [0.03%] permanent

Jamal 7543180 Saudi Arabia

prosp ncrs [TT] nr 54.2 0 [100] 3 months 40 [76] 17.50% nr

Kinnari 20122337 Finland

prosp rct (2001-2002) Xomed Soileau Tytan 4.1[0.5,

15] 61 36[64] until extrusion or removal

170[298] [37%] tubes blocked at 9 months

Luo 25465449 China

prosp nrcs (2011-2012) [tympanostomy tube insertion]

4.80 (1.00) [2.00, 8.00]

50.9 nr 2 years 55 9.09% tube blockage

Mackenzie 6541254 UK

prosp cohort (1978-1980)

Pappas 1974, Shah 1971 (Exmoor 142, Shepard 137, Bobbin 132, Arrow 58, Shah 131, Armstrong 138, Colar Button 141, Paparella 60)

10.80 [0.75, 77.00]

58.3 0 [100] 2.25 years 588 [939] [17.15%] not patent at 3

month f/u

Powell 25598389 UK

prosp cohort (2004-2005) nr 4.60 nr nr 9 weeks to

10 years 89 8.99% blocked tube at 9 weeks

Roland 14702493 US, Canada

prosp rct nr 2.45 [0.50, 12.00]

62.3 nr 18 days 599 0.17% tube blocakge

Saki 24303379 Iran

prosp cohort (2009-2011) nr [0.83,

6.00] 55.8 0 [100] 12 to 18 months 208 3.85%

obstruction of the VT on the tympanic membrane

Smillie 25171763 Scotland

nrcs (2002-2012)

[no cleft lip palate; underwent VT insertion]

med 3.50 [0.60, 10.40]

55 nr nr 60 1.67% grommet occlusion-wax

H-14

Author PMID Country

Design (recruitment

period) Tube Type [arm desc.]

Age (SD) [min, max]

% male

%rAOM [%COME] Followup N [ears] % Tube

Blockage Defintion

Spielmann 18047760 UK

prosp cohort (2003-2004) nr [second cohort]

5.30 [0.83, 9.00]

61.4 18.8 [81.2] 3 months 84 [195] 10.71% nr

Walker 9287928 Australia

prosp cohort Shepard grommet, Shah vent tube, Sheehy collar button vent tube

3.80 nr 12 [85] until extrusion 106 [2.83%] lumenal

obstruction

Wallace 15533143 UK

prosp rct (2001-2002) Shepard or T tube

6.00 [1.00, 13.00]

63.6 75.8 1 month 26 [6.52%] 1 month follow up

Weigel 2645490 US

prosp cohort (1983-1984)

Goode T-tubes, Armstrong Teflon, Reuter-Bobbin Stainless Steel, Shepard Teflon

3.80 [0.60, 13.00]

59 45 [41] 21 months 75 [150] [37.33%] temporary or permanent

Table H5. Granulation tissue Author PMID

Country

Design (recruitment

period) Tube Type [arm desc.]

Age (SD) [min, max]

% male

%rAOM [%COME] Followup N [ears]

% Granulation

Tissue

Defintion Granulation

Tissue Bernard 1991 1861917 Canada

prosp rct (nr) Reuter bobbin, Richart "T" 4.7 56.7 nr 18 months 60 3.3

purulent discharge and granuloma formation

Birck 1267356 US

prosp cohort (1972-1974) nr nr 59.2 nr 6+ months 736

[2327] [0.17%]

Eliachar 6613541 Israel

prosp cohort (1975-1981)

Goode long-term T-shaped silicone design tubes

8.33 [4.50, 16.00]

nr nr 8 to 72 months

122 [203] [5.91%] local granuloma

Kinnari 20122337 Finland

prosp rct (2001-2002) Xomed Soileau Tytan 4.1[0.5,

15] 61 36[64] until extrusion or removal

170[298] [20.1%] nr

Levinson 6819525 US prosp cohort [1.00,

11.00+] nr nr 5 months 64 [124] [5.65%] granulations and discharge

Luo 25465449 China

prosp nrcs (2011-2012)

[tympanostomy tube insertion]

4.80 (1.00) [2.00, 8.00]

50.9 nr 2 years 55 12.73% granulation formation

Muenker 6778334 Germany

prosp cohort (1966-1978) nr nr nr nr nr 631

[1060] [1.79%]

Plotkin 7195446 US

prosp cohort (1977-1979)

Castelli membrane, Donaldson design, silicone tube (Xomed

5.20 [2.50, 11.00]

60.7 0 [100] nr 89 [162] [1.85%] polypoid granulations fromed around the tube

H-15

Author PMID

Country

Design (recruitment

period) Tube Type [arm desc.]

Age (SD) [min, max]

% male

%rAOM [%COME] Followup N [ears]

% Granulation

Tissue

Defintion Granulation

Tissue XO-1201)

Saki 24303379 Iran

prosp cohort (2009-2011) nr [0.83,

6.00] 55.8 0 [100] 12 to 18 months 208 3.37% nr

Smillie 25171763 Scotland

nrcs (2002-2012)

[no cleft lip palate; underwent VT insertion]

med 3.50 [0.60, 10.40]

55 nr nr 60 1.67%

Tavin 3372141 US

prosp cohort (1982-1985) various

4.80 (1.50) [0.33, 16.00]

63.2 nr 365 to 728 days 95 [187] [2.14%]

resulted in granuloma formation between 90 and 183 days

Valtonen 10435125 Finland

prosp cohort (1983-1984)

Shah vent Teflon tube, inner diameter 1.1 mm

0.84 [0.42, 1.33]

58.4 34.2 [65.8] 5 years 281 [281] [5.69%]

Table H6. Premature extrusion Author PMID

Country Design

(recruitment period)

Tube Type [arm desc.]

Age (SD) [min, max]

% male

%rAOM [%COME] Followup N [ears]

% Premature Extrusion

Definition Premature Extrucsion

van Baarle 1169745 Netherlands

prosp cohort Double-flanged, Silastic tubes (Richards)

nr nr nr 12+ weeks 60 13.33%

Brown 8231117 US cohort Goode T-tubes nr nr nr 6 months 168

[328] 0.00% premature extrusion

Daly 12759263 US

prosp cohort (1987-1990) nr [0.50,

8.00] 61 nr 3 to 8 years 138 [275] [56.00%] nr

Eliachar 6613541 Israel

prosp cohort (1975-1981)

Goode long-term T-shaped silicone design tubes

8.33 [4.50, 16.00]

nr nr 8 to 72 months

122 [203] 81.82% extruded

spontaneously

Hammaren-Malmi 17582514 Finland

prosp cohort (2001-2002) nr

1.90 [1.00, 4.00]

54 nr 12 months 217 73.74%

tympanostomy tube lost or non-patent during follow-up (12 months)

Heaton 8877228 UK

prosp cohort (1986-1988) nr

5.00 [1.00, 12.00]

60.6 0 [100] nr 127 34.65% undergone insertion of a subsequent tube or tubes

Ida 19324425 US prosp cohort pressure

equalization tube [0.67, 4.00] nr 0 [100] 16 months 50 58.00% nr

Khan 16773972 Pakistan

prosp cohort (2001-2003) nr [2.00,

40.00] 66.6 0 [100] 18 to 24 months 57 [114] [0.88%] nr

H-16

Author PMID Country

Design (recruitment

period) Tube Type [arm

desc.] Age (SD)

[min, max]

% male

%rAOM [%COME] Followup N [ears]

% Premature Extrusion

Definition Premature Extrucsion

Kinnari 20122337 Finland

prosp rct (2001-2002)

Xomed Soileau Tytan

4.1[0.5, 15] 61 36[64]

until extrusion or removal

170[298] [3.9%] within 3 months

Kokko 1267359 Finland

cohort (1965-1971) nr nr nr nr 3.167 years

(average) [290] [0.24%] nr

MacKinnon 4105168 UK

prosp cohort (1965-1971) nr =<16.00 nr nr nr 95 [165] 37.89%

[39.39%]

requiring grommets on more than one occassion

Paradise 2181158 US

prosp rct/nrcs (1971-1985)

[TT & Adenoidectomy] nr 67 nr nr 97 [5.60%]

perforations remaining unhealed for periods of 10 months to 4.5 years

Praveen 15992470 UK

prosp cohort (1998-2003)

Shah ventilation tubes

5.00 [1.60, 14.50]

64 nr nr 606 [1174] 8.42% early extrusions

Saki 24303379 Iran

prosp cohort (2009-2011) nr [0.83,

6.00] 55.8 0 [100] 12 to 18 months 208 5.77% early extrusion from

the membrane

Spielmann 18047760 UK

prosp cohort (2003-2004) nr [second cohort]

5.30 [0.83, 9.00]

61.4 18.8 [81.2] 3 months 84 [195] 10.71% nr

Tuli 23119801 India cohort nr nr 66.7 0 [100] nr 100 4.00% early dislocation of

grommet

Valtonen 10435125 Finland

prosp cohort (1983-1984)

Shah vent Teflon tube, inner diameter 1.1 mm

0.84 [0.42, 1.33]

58.4 34.2 [65.8] 5 years 281 [281] [1.78%]

ventilation tube extruded early, within two weeks post-operatively

Wallace 15533143 UK

prosp rct (2001-2002) Shepard or T tube

6.00 [1.00, 13.00]

63.6 75.8 1 month 26 [4.35%] 1 month

Table H7. TT displacement Author PMID

Country

Design (recruitment

period) Tube Type [arm desc.]

Age (SD) [min, max]

% male

%rAOM [%COME] Followup N [ears] % TT

Displacement Definition TT displacement

Birck 1267356 US

prosp cohort (1972-1974) nr nr 59.2 nr 6+ months 736

[2327] [0.60%] tubes in tympanum

Fiebach 3570884 Germany

prosp cohort (1979-1984) nr [1.00,

6.00] 60.5 nr nr 534 [1000] 0.37% nr

Fior 6526581

prosp cohort (1968-1978) Shepard type 3.00

[0.33, 60.6 100 [0] 5 to 15 years 61 [108] [0.93%] Migration of the

tube into the

H-17

Author PMID

Country

Design (recruitment

period) Tube Type [arm desc.]

Age (SD) [min, max]

% male

%rAOM [%COME] Followup N [ears] % TT

Displacement Definition TT displacement

Italy 6.00] tympanic cavity Kinnari 20122337 Finland

prosp rct (2001-2002) Xomed Soileau Tytan 4.1[0.5,

15] 61 36[64] until extrusion or removal

170[298] 0.00% nr

Kokko 1267359 Finland

cohort (1965-1971) nr nr nr nr 3.167 years

(average) [290] [0.69%] slippage of TT into tympanum

Mackenzie 6541254 UK

prosp cohort (1978-1980)

Pappas 1974, Shah 1971 (Exmoor 142, Shepard 137, Bobbin 132, Arrow 58, Shah 131, Armstrong 138, Colar Button 141, Paparella 60)

10.80 [0.75, 77.00]

58.3 0 [100] 2.25 years 588 [939] [2.34%] nr

Muenker 6778334 Germany

prosp cohort (1966-1978) nr nr nr nr nr 631

[1060] [0.75%] extrusion into the tympanic cavity

Saki 24303379 Iran

prosp cohort (2009-2011) nr [0.83,

6.00] 55.8 0 [100] 12 to 18 months 208 0.48% displacement into

the middle ear

Table H8. Persistent perforation Author PMID

Country Design

(recruitment period)

Tube Type [arm desc.] Age (SD)

[min, max]

% male

%rAOM [%COME] Followup N [ears]

% Persistent Perforation

Definition Persistent Perforation

van Baarle 1169745 Netherlands

prosp cohort Double-flanged, Silastic tubes (Richards) nr nr nr 12+ weeks 60 1.67%

perforation remained 2 months later

Barfoed 7190819 Denmark

prosp cohort (nr) nr nr 57 0[100] 4.5 to 7.5

years 90[173] nr[5.00%] central perforations without suppuration

Bernard 1991 1861917 Canada

prosp rct (nr) Reuter bobbin, Richart "T" 4.7 56.7 nr 18 months 60 0.00% nr

Birck 1267356 US

prosp cohort (1972-1974) nr nr 59.2 nr 6+ months 736

[2327] 1.90% nr

Brown 8231117 US cohort Goode T-tubes nr nr nr 6 months 168

[328] [2.44%]

perforations persisted in tympanic membranes after extraction

H-18

Author PMID Country

Design (recruitment

period) Tube Type [arm desc.]

Age (SD) [min, max]

% male

%rAOM [%COME] Followup N [ears]

% Persistent Perforation

Definition Persistent Perforation

Carignan 17049144 Canada

prosp cohort (2003-2004) Goode T-tubes 5.70 62 71 [29] 18 months nr 1.79%

perforations persisted > 6 months

Casselbrant 1565551 US

prosp rct (1981-1988) Teflon Armstrong-type TT nr 58.1 100[0] 2 years 86 13%

perforation after spontaneous extrusion

Costa 3472336 Brazil prosp cohort nr nr nr 0 [100] nr 79 2.53% perforation of the

eardrum Daly 12759263 US

prosp cohort (1987-1990) nr [0.50,

8.00] 61 nr 3 to 8 years 138 [275] [67.64%] perforation

De Beer 15224825 Netherlands

prosp cohort (1982-1983) nr nr 47 nr 18 years 51 [101] [5.94%]

De Beer 16151352 Netherlands

prosp ncrs [positive history of otitis media and ventilation tube insertion]

nr nr nr 16 years 51[102] [6.78%] at 18 years old

Debruyne 3177616 Belgium

prosp cohort nr 4.92 nr 45.2% [54.8]

until extrusion

906 [1685] 1.14%

perforations persisted > 6 months

Debruyne 3799183 Belgium

cohort nr 2.70+ 55.4 nr 0.5 to 6 years

906 [1685] [1.27%]

perforations persisted > 6 months

Eliachar 6613541 Israel

prosp cohort (1975-1981)

Goode long-term T-shaped silicone design tubes

8.33 [4.50, 16.00]

nr nr 8 to 72 months

122 [203] [3.94%]

permanent unhealed perforations

Fiebach 3570884 Germany

prosp cohort (1979-1984) nr [1.00,

6.00] 60.5 nr nr 534 [1000] [0.94%]

lasting perforation of the tympanic membrane

Fior 6526581 Italy

prosp cohort (1968-1978) Shepard type

3.00 [0.33, 6.00]

60.6 100 [0] 5 to 15 years 61 [108] [5.56%]

Persistent perforation of the tympanic membrane following extrusion of the tube

Florentzson 22648089 Sweden

prosp cohort (1/1996-12/1996)

Tympovent 0.9 mm diameter straight fluoroplastic tube from Atos Medical

3.90 61 nr 10 years 155 [280] [2.1%] permanent

perforations

Golz 10187945 US, Israel

retro cohort (1980-1994)

93% standard polyethylene tubes, 7% Goode T tubes

4.20 (1.40) [0.83,

55 91 [7.5] at least 1 year after extrusion or

1360 [2604] [3.06%]

H-19

Author PMID Country

Design (recruitment

period) Tube Type [arm desc.]

Age (SD) [min, max]

% male

%rAOM [%COME] Followup N [ears]

% Persistent Perforation

Definition Persistent Perforation

10.00] removal Hampton 9118580 Ireland

prosp cohort Armstrong ventilation tubes

[0.75, 10.25] 58.7 nr 17 months

(mean) 109 [218] [2.75%]

tympanic membrane perforations

Hörmann 1816937 Germany

prosp nrcs [cleft palate - University of Hamburg]

7.43 [5.00, 10.00]

nr nr 8 years 126 [252] 8.73%

Khan 16773972 Pakistan

prosp cohort (2001-2003) nr [2.00,

40.00] 66.6 0 [100] 18 to 24 months 57 [114] 2.63% nr

Kinnari 20122337 Finland

prosp rct (2001-2002) Xomed Soileau Tytan 4.1[0.5,

15] 61 36[64] until extrusion or removal

170[298] [0.7%] nr

Kokko 1267359 Finland

cohort (1965-1971) nr nr nr nr 3.167 years

(average) [290] [1.72%]

dry perforation (central 2-3 mm pars tensa defect); perforation with discharge

Levine 8179266 US prosp cohort

Donaldson, Shephard, Paparella or Reuter/bobbin

[0.50, 8.00] nr 0 [100] 4 years

(mean) 149 14.09% tympanic membrane perforations

Mackenzie 6541254 UK

prosp cohort (1978-1980)

Pappas 1974, Shah 1971 (Exmoor 142, Shepard 137, Bobbin 132, Arrow 58, Shah 131, Armstrong 138, Colar Button 141, Paparella 60)

10.80 [0.75, 77.00]

58.3 0 [100] 2.25 years 588 [939] 0.34% perforation at long

term f/u

MacKinnon 4105168 UK

prosp cohort (1965-1971) nr =<16.00 nr nr nr 95 [165] [3.03%]

perforation after removal of grommets

Mandel 2789777 US

prosp rct (1979-1984) Teflon Armstrong-type TT nr nr 0[100] until

extrusion 63[102] [11.7%] perforation after spontaneous extrusion

Muenker 6778334 Germany

prosp cohort (1966-1978) nr nr nr nr nr 631

[1060] [2.45%]

O'Niel 26115935 US

prosp cohort (2009-nr)

various, including Sheehy, Armstrong, T tube, Activent

3 (2.8) [0.08 - 17'

42.4 60[38] 1 year post TT extrusion 634[544] 1.10% post-extrusion

performation

Paradise 11309632 US

prosp rct (1991-1995)

Armstrong [TT early treatment; underwent TT insertion at initiaition of

5.00 52.6 0 [100] ~2 years 121 [242]

4.96% [2.48%]

perforation with or without other abnormality

H-20

Author PMID Country

Design (recruitment

period) Tube Type [arm desc.]

Age (SD) [min, max]

% male

%rAOM [%COME] Followup N [ears]

% Persistent Perforation

Definition Persistent Perforation

symptoms]

Pereira 16446953 Brazil

prosp cohort (2001-2002)

Short-term ventilation tubes, made of silicone, measuring 1.2 x 2.6 mm, type Donaldson

2.89 (1.54) [0.92, 9.33]

60 69.3 [30.7] 38 months 75 [150] [2.05%]

Plotkin 7195446 US

prosp cohort (1977-1979)

Castelli membrane, Donaldson design, silicone tube (Xomed XO-1201)

5.20 [2.50, 11.00]

60.7 0 [100] nr 89 [162] [2%] perforation for ≥ 6 months

Postma 9350484 US

prosp cohort (1988-1991)

Amstrong grommt or straight Armstrong nr nr nr until

extruded 346 5.20% nr

Powell 25598389 UK

prosp cohort (2004-2005) nr 4.60 nr nr 9 weeks to

10 years 89 6.67%

Rothera 4040147 UK

prosp cohort (1980-1982)

Xomed silicone Goode T-Tubes (1.1 mm. internal diameter, 12 mm. length)

nr nr 0 [100] 30 months 73 [131] [3.82%] central perforations

Saki 24303379 Iran

prosp cohort (2009-2011) nr [0.83,

6.00] 55.8 0 [100] 12 to 18 months 208 2.40%

Siddiqui 9225174 UK

prosp cohort (1987-1992) Mangat tube (Xomed)

mode 5.00 [0.50, 14.00]

61.8 0 [100] 3 years 191 [322] [5.28%] perforation at a

year follow-up

Smillie 25171763 Scotland

nrcs (2002-2012)

[no cleft lip palate; underwent VT insertion]

med 3.50 [0.60, 10.40]

55 nr nr 60 5.00% tympanic membrane perforation

Suetake 2239252 Japan

prosp cohort (1986-1987) nr

6.20 (2.00) [3.00, 11.00]

59.6 0 [100] nr 52 [90] [14.55%] nr

Tos 985199 Denmark prosp cohort nr nr 14 nr 1 to 8 years 109 2.75%

Tuli 23119801 India cohort nr nr 66.7 0 [100] nr 100 8.00% permanent

perforation Valtonen 10435125 Finland

prosp cohort (1983-1984)

Shah vent Teflon tube, inner diameter 1.1 mm

0.84 [0.42, 1.33]

58.4 34.2 [65.8] 5 years 281 [281] [2.49%]

Valtonen 12150521 Finland

prosp cohort (1983-1984)

Shah vent Teflon tube, inner diameter 1.1 mm

0.84 [0.42, 1.33]

58.4 34.2 [65.8] 5 years 281 [281] [4.63%]

Valtonen prosp cohort Shah vent Teflon tube nr 51.4 0 [100] 5 to 7.2 72 [124] 6.94% nr

H-21

Author PMID Country

Design (recruitment

period) Tube Type [arm desc.]

Age (SD) [min, max]

% male

%rAOM [%COME] Followup N [ears]

% Persistent Perforation

Definition Persistent Perforation

16094135 Finland

(1983-1993) (Xomed) years

Van Cauwenberge 576016 Belgium

prosp cohort nr [2.00, 14.00] 49.3 0 [100] 5 to 120

months 148 2.70%

Velepic 21397957 Croatia

prosp rct (2004-2009) nr

5.44 [2.00, 12.00]

nr 0 [100] nr [161] [0.00%] eardrum peforation

Walker 9287928 Australia

prosp cohort Shepard grommet, Shah vent tube, Sheehy collar button vent tube

3.80 nr 12 [85] until extrusion 106 [0.47%]

Weigel 2645490 US

prosp cohort (1983-1984)

Goode T-tubes, Armstrong Teflon, Reuter-Bobbin Stainless Steel, Shepard Teflon

3.80 [0.60, 13.00]

59 45 [41] 21 months 75 [150] [6.00%]

Table H9. Myringosclerosis Author PMID Country

Design (recruitment period)

Tube Type [arm desc.]

Age (SD) [min, max]

% male

%rAOM [%COME] Followup N

[ears] % Myringosclerosis def_myringosclerosis

Koc 11271428 Turkey

prosp cohort (1988-1997)

Paparella type-1, type-2, Shepard Grommet or Modified T tympanostomy tubes

nr 58 nr nr 251 [431] [49.88%] nr

Barfoed 7190819 Denmark

prosp cohort (nr) nr nr 57 0[100] 4.5 to 7.5

years 90[173] nr[23%] tympanosclerosis along the whole anulus

Bernard 1991 1861917 Canada

prosp rct (nr) Reuter bobbin, Richart "T" 4.7 56.7 nr 18

months 60 28.3 localized without involvement of middle ear structures

Birck 1267356 US

prosp cohort (1972-1974) nr nr 59.2 nr 6+

months 736 [2327] 0.95% tympanosclerosis (43

tube insertions) Daly 12759263 US

prosp cohort (1987-1990) nr [0.50,

8.00] 61 nr 3 to 8 years

138 [275] [49.82%] myringosclerosis

Daly 9738746 US

cross-sectional (1985-1990)

[children treated with TT]

17.70 (3.50) [13.00,

61 0 [100] nr 108 61.00% 8- to 12-year-olds

H-22

Author PMID Country

Design (recruitment period)

Tube Type [arm desc.]

Age (SD) [min, max]

% male

%rAOM [%COME] Followup N

[ears] % Myringosclerosis def_myringosclerosis

28.00] De Beer 15224825 Netherlands

prosp cohort (1982-1983) nr nr 47 nr 18 years 51

[101] [64.36%]

De Beer 16151352 Netherlands

prosp ncrs [positive history of otitis media and ventilation tube insertion]

nr nr nr 16 years 51[102] 55.93% at 18 years

Fiebach 3570884 Germany

prosp cohort (1979-1984) nr [1.00,

6.00] 60.5 nr nr 534 [1000] [11.29%] scarring or calcification

Friedman 11551611 US

prosp cohort nr [0.08, 30.00] 60.1 nr nr 81 34.57% tympanosclerosis in at

least one ear

Gundersen 1267702 Norway

prosp cohort polyethylene ventilating tube

7.50 [1.00, 14.00]

nr 0 [100] 2 to 11 years

100 [196] [11.22%]

Khan 16773972 Pakistan

prosp cohort (2001-2003) nr [2.00,

40.00] 66.6 0 [100] 18 to 24 months

57 [114] [5.26%] nr

Luo 25465449 China

prosp nrcs (2011-2012)

[tympanostomy tube insertion]

4.80 (1.00) [2.00, 8.00]

50.9 nr 2 years 55 34.55% myringosclerosis

Mackenzie 6541254 UK

prosp cohort (1978-1980)

Pappas 1974, Shah 1971 (Exmoor 142, Shepard 137, Bobbin 132, Arrow 58, Shah 131, Armstrong 138, Colar Button 141, Paparella 60)

10.80 [0.75, 77.00]

58.3 0 [100] 2.25 years

588 [939] 0.68% tympanosclerosis at long

term f/u

Paradise 11309632 US

prosp rct (1991-1995)

Armstrong [TT early treatment; underwent TT insertion at initiaition of symptoms]

5.00 52.6 0 [100] ~2 years 121 [242] 3.31% [4.13%] tympanosclerosis

Pereira 16446953 Brazil

prosp cohort (2001-2002)

Short-term ventilation tubes, made of silicone, measuring 1.2 x 2.6 mm, type Donaldson

2.89 (1.54) [0.92, 9.33]

60 69.3 [30.7] 38 months

75 [150] [2.74%] nr

Saki prosp cohort nr [0.83, 55.8 0 [100] 12 to 18 208 37.98% nr

H-23

Author PMID Country

Design (recruitment period)

Tube Type [arm desc.]

Age (SD) [min, max]

% male

%rAOM [%COME] Followup N

[ears] % Myringosclerosis def_myringosclerosis

24303379 Iran

(2009-2011) 6.00] months

Slack 6470572 UK prosp cohort Shepard grommet [4.00,

10.00] nr nr 21 months 124 56.45% nr

Smillie 25171763 Scotland

nrcs (2002-2012)

[no cleft lip palate; underwent VT insertion]

med 3.50 [0.60, 10.40]

55 nr nr 60 5.00% nr

Tos 3814387 Denmark

prosp cohort (1970-1975) nr nr nr nr nr 278

[527] 33.45% nr

Tos 985199 Denmark prosp cohort nr nr 14 nr 1 to 8

years 109 22.94% diffuse tympanosclerosis

Velepic 21397957 Croatia

prosp rct (2004-2009) nr

5.44 [2.00, 12.00]

nr 0 [100] nr [161] [26.09%] nr

Table H10. Atrophy or atelectasis or retraction Author PMID

Country Design

(recruitment period)

Tube Type [arm desc.]

Age (SD) [min, max]

% male

%rAOM [%COME] Followup N [ears]

% Atrophy Atelectasis Retraction

Definition

Barfoed 7190819 Denmark

prosp cohort (nr) nr nr 57 0[100] 4.5 to 7.5

years 90[173] [25.00%] atrophy at the former grommet site, anteriorly

Bonding 4215997 US

cohort (1967-1969) nr [=<3.00,

4.00] 66.7 0 [100] 16 to 48 months

108 [175] 13.89% diffuse atrophy of the

tympanic membrane Bonding 4702615 Denmark

cohort nr nr 66.7 0 [100] nr 117 [188] 8.55% atrophic drum

Daly 12759263 US

prosp cohort (1987-1990) nr [0.50,

8.00] 61 nr 3 to 8 years

138 [275] [66.18%] atrophy

Daly 9738746 US

cross-sectional (1985-1990)

[children treated with TT]

17.70 (3.50) [13.00, 28.00]

61 0 [100] nr 108 4.00% severe TM retraction

De Beer 16151352 Netherlands

prosp ncrs

[positive history of otitis media and ventilation tube insertion]

nr nr nr 16 years 51[102] 20.34% atrophy at 18 years

Eliachar 6613541

prosp cohort (1975-1981)

Goode long-term T-shaped silicone

8.33 [4.50, nr nr 8 to 72

months 122 [203] 100.00% retraction pockets (75 in

the attic, 82 - both in the

H-24

Author PMID Country

Design (recruitment

period) Tube Type [arm

desc.] Age (SD)

[min, max]

% male

%rAOM [%COME] Followup N [ears]

% Atrophy Atelectasis Retraction

Definition

Israel design tubes 16.00] attic and posterior superior quandrant and 38 had other variations)

Fior 6526581 Italy

prosp cohort (1968-1978) Shepard type

3.00 [0.33, 6.00]

60.6 100 [0] 5 to 15 years 61 [108] [5.56%] tympanic atrophy

Hörmann 1816937 Germany

prosp nrcs [cleft palate - University of Hamburg]

7.43 [5.00, 10.00]

nr nr 8 years 126 [252] 6.35% retraction and atrophy

Li 10547462 US

prosp cohort (1987-1991)

Donaldson tubes, Reuter Bobbin tubes, Shepard tubes or other

nr 57 0 [100] 4 to 6 years

109 [214] 42.86% severe pars tensa

retraction

O'Niel 26115935 US

prosp cohort (2009-nr)

various, including Sheehy, Armstrong, T tube, Activent

3 (2.8) [0.08 - 17' 42.4 60[38]

1 year post TT extrusion

634[544] 24.00% nr

Paradise 11309632 US

prosp rct (1991-1995)

Armstrong [TT early treatment; underwent TT insertion at initiaition of symptoms]

5.00 52.6 0 [100] ~2 years 121 [242] [40.08%] segmental atrophy

Pereira 16446953 Brazil

prosp cohort (2001-2002)

Short-term ventilation tubes, made of silicone, measuring 1.2 x 2.6 mm, type Donaldson

2.89 (1.54) [0.92, 9.33]

60 69.3 [30.7] 38 months 75 [150] 39.73% nr

Powell 25598389 UK

prosp cohort (2004-2005) nr 4.60 nr nr 9 weeks to

10 years 89 12.00% tympanic membrane retraction pocket

Praveen 15992470 UK

prosp cohort (1998-2003)

Shah ventilation tubes

5.00 [1.60, 14.50]

64 nr nr 606 [1174] [4.43%] attic reaction

postoperatively

Saki 24303379 Iran

prosp cohort (2009-2011) nr [0.83,

6.00] 55.8 0 [100] 12 to 18 months 208 27.88% tympanic membrane

atrophy

Smillie 25171763 Scotland

nrcs (2002-2012)

[no cleft lip palate; underwent VT insertion]

med 3.50 [0.60, 10.40]

55 nr nr 60 2.33% retracted tympanic membrane; attic retraction

Tos 3814387 prosp cohort nr nr nr nr nr 278 [14.36%] atrophy

H-25

Author PMID Country

Design (recruitment

period) Tube Type [arm

desc.] Age (SD)

[min, max]

% male

%rAOM [%COME] Followup N [ears]

% Atrophy Atelectasis Retraction

Definition

Denmark (1970-1975) [527]

Tos 985199 Denmark prosp cohort nr nr 14 nr 1 to 8

years 109 5.50%

Adhesive otitis with retracted, immobile drum, an entirely or partially atelectatic middle ear, and poor tubal function

Valtonen 12150521 Finland

prosp cohort (1983-1984)

Shah vent Teflon tube, inner diameter 1.1 mm

0.84 [0.42, 1.33]

58.4 34.2 [65.8] 5 years 281 [281] 16.73%

retraction of pars flaccida (20); retraction of pars tensa (27)

Valtonen 16094135 Finland

prosp cohort (1983-1993)

Shah vent Teflon tube (Xomed) nr 51.4 0 [100] 5 to 7.2

years 72 [124] 12.50% pars tensa retraction of tympanic membrane

Velepic 21397957 Croatia

prosp rct (2004-2009) nr

5.44 [2.00, 12.00]

nr 0 [100] nr [161] [3.11%] Severe Attic retractions

Table H11. Cholesteotoma Author PMID

Country

Design (recruitment

period) Tube Type [arm

desc.] Age (SD)

[min, max]

% male

%rAOM [%COME] Followup N [ears] %

Cholesteotoma def_cholesteotoma

Barfoed 7190819 Denmark

prosp cohort (nr) nr nr 57 0[100] 4.5 to 7.5

years 90[173] 0% nr

Birck 1267356 US

prosp cohort (1972-1974) nr nr 59.2 nr 6+

months 736 [2327] [0.00%] nr

Bonding 4215997 US

cohort (1967-1969) nr [=<3.00,

4.00] 66.7 0 [100] 16 to 48 months

108 [175] 1.85%

suppurative otitis media with cholesteatoma

Djurhuus 25724629 Denmark

retro cohort (1997-2011)

various [data from National Registers nr nr nr nr 217206 0.17% surgically treated

Eliachar 6613541 Israel

prosp cohort (1975-1981)

Goode long-term T-shaped silicone design tubes

8.33 [4.50, 16.00]

nr nr 8 to 72 months

122 [203] [1.48%]

developed cholesteatoma in their pre-existing retractions pockets

Golz retro cohort "homemade" 4.80 54.4 11.4 1 to 20 2829 2.19% nr

H-26

Author PMID

Country

Design (recruitment

period) Tube Type [arm

desc.] Age (SD)

[min, max]

% male

%rAOM [%COME] Followup N [ears] %

Cholesteotoma def_cholesteotoma

10406312 Israel

(1978-1997) polyethylene tubes in 5143 ears, Goode T-tubes in 432 ears

(2.60) [1.20, 14.00]

(ears) [88.6 (ears)]

years [5575]

Gundersen 1267702 Norway

prosp cohort polyethylene ventilating tube

7.50 [1.00, 14.00] nr 0 [100] 2 to 11

years 100 [196] [5.61%] cholesteatoma

Heaton 8877228 UK

prosp cohort (1986-1988) nr 5.00 [1.00,

12.00] 60.6 0 [100] nr 127 0.79% nr

Hörmann 1816937 Germany

prosp nrcs [cleft palate - University of Hamburg]

7.43 [5.00, 10.00] nr nr 8 years 126

[252] 0.00% nr

Kinnari 20122337 Finland

prosp rct (2001-2002)

Xomed Soileau Tytan

4.1[0.5, 15] 61 36[64]

until extrusion or removal

170[298] 0.00%

Kokko 1267359 Finland

cohort (1965-1971) nr nr nr nr

3.167 years (average)

[290] [0.69%] attic cholesteatoma

Luo 25465449 China

prosp nrcs (2011-2012)

[tympanostomy tube insertion]

4.80 (1.00) [2.00, 8.00]

50.9 nr 2 years 55 10.91% cholesteatoma in the attic

MacKinnon 4105168 UK

prosp cohort (1965-1971) nr =<16.00 nr nr nr 95 [165] 6.32% [4.85%]

cholesteatoma after previous exudative otitis media

Muenker 6778334 Germany

prosp cohort (1966-1978) nr nr nr nr nr 631

[1060] 1.58%

preexisting cholesteatoma was revealed behind an intact tympanic membrane on 3 occasions

O'Niel 26115935 US

prosp cohort (2009-nr)

various, including Sheehy, Armstrong, T tube, Activent

3 (2.8) [0.08 - 17' 42.4 60[38]

1 year post TT extrusion

634[544] 0.56% nr

Paradise 2181158 US

prosp rct/nrcs (1971-1985)

[TT & Adenoidectomy] nr 67 nr nr 97 0.80% nr

Pereira 16446953 Brazil

prosp cohort (2001-2002)

Short-term ventilation tubes, made of silicone, measuring 1.2 x 2.6 mm, type Donaldson

2.89 (1.54) [0.92, 9.33]

60 69.3 [30.7] 38 months 75 [150] [0.00%] nr

H-27

Author PMID

Country

Design (recruitment

period) Tube Type [arm

desc.] Age (SD)

[min, max]

% male

%rAOM [%COME] Followup N [ears] %

Cholesteotoma def_cholesteotoma

Powell 25598389 UK

prosp cohort (2004-2005) nr 4.60 nr nr 9 weeks to

10 years 89 1.33% otolaryngology-clinic-diagnosed cholesteatoma

Rothera 4040147 UK

prosp cohort (1980-1982)

Xomed silicone Goode T-Tubes (1.1 mm. internal diameter, 12 mm. length)

nr nr 0 [100] 30 months 73 [131] 0.00% nr

Smillie 25171763 Scotland

nrcs (2002-2012)

[no cleft lip palate; underwent VT insertion]

med 3.50 [0.60, 10.40]

55 nr nr 60 3.33% posterior pars tensa cholesteatoma

Spilsbury 23737350 Austalia

retro cohort (1980-2009) nr nr 59.7 nr 11.9 years 56949 1.04% nr

Tos 3814387 Denmark

prosp cohort (1970-1975) nr nr nr nr nr 278

[527] [0.28%] attic cholesteatoma

Tos 7192477 Denmark

cohort Armstrong tube nr nr 0 [100] 6 months [527] 0.20% deep retraction pocket, the bottom of which could not be seen

Tos 985199 Denmark

prosp cohort nr nr 14 nr 1 to 8 years 109 1.83% cholesteatoma in the

attic

Table H12. Hearing loss Author PMID

Country

Design (recruitment

period) Tube Type [arm desc.]

Age (SD) [min, max]

% male

%rAOM [%COME] Followup N

[ears] %

Hearing Loss

Definition

Brown 8231117 US cohort Goode T-tubes nr nr nr 6 months 168

[328] 1.19% conductive hearing loss

Costa 3472336 Brazil

prosp cohort nr nr nr 0 [100] nr 79 1.27% unilateral sensorineural hearing loss

Daly 12759263 US

prosp cohort (1987-1990) nr [0.50,

8.00] 61 nr 3 to 8 years

138 [275] [91.27%] hearing loss

Daly 9738746 US

cross-sectional [children treated with TT] 17.70

(3.50) 61 0 [100] nr 108 10.00% nr

H-28

Author PMID

Country

Design (recruitment

period) Tube Type [arm desc.]

Age (SD) [min, max]

% male

%rAOM [%COME] Followup N

[ears] %

Hearing Loss

Definition

(1985-1990) [13.00, 28.00]

Gundersen 1267702 Norway

prosp cohort polyethylene ventilating tube

7.50 [1.00, 14.00]

nr 0 [100] 2 to 11 years

100 [196] [20.92%]

hearing was not normal, varying from a pure-tone average (PTA) of 25 to 60 dB hearing level (PTA was measured as the mean hearing loss for the frequencies 500, 1,000 and 2,000 hertz.)

Isaacson 18722211 US

prosp cohort (1997-2007)

Armstrong beveled grommet tube

[0.11, 21.00] nr nr nr [10000] 0.02%

profound hearing loss, both were found to have Mondini malformations by CT

Mackenzie 6541254 UK

prosp cohort (1978-1980)

Pappas 1974, Shah 1971 (Exmoor 142, Shepard 137, Bobbin 132, Arrow 58, Shah 131, Armstrong 138, Colar Button 141, Paparella 60)

10.80 [0.75, 77.00]

58.3 0 [100] 2.25 years

588 [939] 28.38% by audiometric assessment at 3

month

Owen 8436453 US prosp cohort Armstrong bevelled tube

2.08 [0.42, 4.00]

nr nr 6 months 52 [98] [7.94%] moderate hearing loss (27.5-50 dB)

Spielmann 18047760 UK

prosp cohort (2003-2004) nr [second cohort]

5.30 [0.83, 9.00]

61.4 18.8 [81.2] 3 months 84 [195] 35.62% a mean hearing threshold

greater than 20 dB

Tuli 23119801 India

cohort nr nr 66.7 0 [100] nr 100 8.00% worsening of hearing

H-29

Appendix I. Network Meta-Analysis Model, Inconsistency Analysis Results, and Illustrative Trace

and Posterior Density Plots The meta-analysis models used in this report are described here in a technical manner. We describe the network meta-analysis model, noting that the simple meta-analysis model is a special case of the network model, setting the number of treatments (nodes) to 2.

Network Meta-Analysis Model The network meta-analysis model is a hierarchical model that has an observational and a structural part (model).

Observational Model

, and

,

with indexing the studies, and indexing treatment arms. is the mean of the modeled continuous outcome in arm of study . is a design matrix corresponding arms to treatment effects. is a column vector of study-specific treatment effects for the treatments versus a reference treatment , which is chosen arbitrarily. is the mean in study for the reference treatment.

Structural Model Between studies, the study-specific treatment effects are modeled with a multivariate normal distribution

, where is a compound symmetry matrix of dimension , with all diagonal elements equal to and all off diagonal elements equal to , and is a column vector of

between-study effect means.

Hyperparameters We used normal hyperpriors for means and a uniform prior for standard deviations. Specifically,

and

where is a column vector of zeros, a conformal identity matrix and and scaling factors that are set to 15 and 5 times the range of observed effects, respectively.

I-1

To check for inconsistency we conducted split node analyses. We replaced each treatment effect that compares the -th treatment with the baseline one , with a direct effect, and an indirect effect, separating the contributions of head-to-head evidence and indirect evidence and examined whether the difference between them was beyond 0.

Inconsistency Analysis Results An ensemble of relevant node-splitting models were generated. Results of direct vs. indirect

vs. entire network are plotted below along with inconsistency Bayesian P values for each split comparison.

Appendix Figure I1. Inconsistency analysis results for KQ1 – early hearing levels

KQ 1: Late Hearing Levels There cannot be inconsistency in this network, given that estimates arise from a single trial

with three arms.

Appendix Figure I2. Inconsistency analysis results for KQ1 – duration of middle ear effusion

Study P-value Mean Difference WW vs Mdirect 1.6 (-9.1, 11.)indirect 0.3886 8.7 (-11., 28.)network 2.3 (-4.1, 9.3)

0-20 30

Study P-value Mean Difference ( M_Ad vs Mdirect -20. (-61., 22.)indirect 0.303775 9.2 ( -36., 56.)network -7.0 ( -35., 22.)TT_Ad vs Mdirect -24. (-67., 18.)indirect 0.5317 -6.1 ( -53., 42.)network -16. ( -44., 13.)WW vs Mdirect 4.1 (-28., 36.)indirect 0.86325 9.1 ( -43., 64.)network 6.9 (-17., 32.)

0-70 70

I-2

Appendix Figure I3. Inconsistency analysis results for KQ5

Appendix Figure I4. Illustrative trace and posterior density plot for KQ5 network meta-analysis

Study P-value Odds Ratio (95% CrI)antibiotic_gtt vs antibiotic_glucocorticoid_gttdirect 0.87 (0.12, 7.)indirect 0.451825 0.30 (0.020, 5.)network 0.61 (0.13, 2.9)oral_antibiotic vs antibiotic_glucocorticoid_gttdirect 0.12 (0.011, 1.4)indirect 0.51145 0.37 (0.013, 9.6)network 0.19 (0.037, 0.86)WW_or_placebo vs antibiotic_glucocorticoid_gttdirect 0.040 (0.0015, 0.99)indirect 0.496725 0.14 (0.0072, 2.5)network 0.085 (0.013, 0.54)

10.001 10

I-3